Reestablishing Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells for Hearing Loss 2021View this Special Issue
Review Article | Open Access
Lingjun Zhang, Zhengde Du, Shusheng Gong, "Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss", Neural Plasticity, vol. 2021, Article ID 5520794, 10 pages, 2021. https://doi.org/10.1155/2021/5520794
Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss
Mitochondrial dysfunction has been suggested to be a risk factor for sensorineural hearing loss (SNHL) induced by aging, noise, ototoxic drugs, and gene. Reactive oxygen species (ROS) are mainly derived from mitochondria, and oxidative stress induced by ROS contributes to cochlear damage as well as mitochondrial DNA mutations, which may enhance the sensitivity and severity of hearing loss and disrupt ion homeostasis (e.g., Ca2+ homeostasis). The formation and accumulation of ROS further undermine mitochondrial components and ultimately lead to apoptosis and necrosis. SIRT3–5, located in mitochondria, belong to the family of sirtuins, which are highly conserved deacetylases dependent on nicotinamide adenine dinucleotide (NAD+). These deacetylases regulate diverse cellular biochemical activities. Recent studies have revealed that mitochondrial sirtuins, especially SIRT3, modulate ROS levels in hearing loss pathologies. Although the precise functions of SIRT4 and SIRT5 in the cochlea remain unclear, the molecular mechanisms in other tissues indicate a potential protective effect against hearing loss. In this review, we summarize the current knowledge regarding the role of mitochondrial dysfunction in hearing loss, discuss possible functional links between mitochondrial sirtuins and SNHL, and propose a perspective that SIRT3–5 have a positive effect on SNHL.
Hearing loss is a common sensory disorder with high prevalence. About 500 million people in the world suffer from hearing loss . It can not only cause impaired communication, but also affect the physical and mental health of individuals and social and economic development. It has been proposed that the elderly with hearing loss have higher rates of dementia, depression, and death . Hearing loss is often classified as conductive, sensorineural, or mixed according to anatomical deficit [2, 3]. Sensorineural hearing loss is caused by dysfunction of cochlea or auditory nerve, which is the commonest in adult primary care [2, 3].
Many previous studies have suggested that mitochondrial dysfunction is involved in the etiology of several types of sensorineural hearing loss (SNHL), such as noised-induced hearing loss (NIHL), age-related hearing loss (ARHL), ototoxic drug-induced hearing loss (ODIHL), and inherited hearing loss. In most mammalian cells, mitochondria are the main source of reactive oxygen species (ROS) [4, 5, 6]. Increased ROS formation results in further damage to the mitochondrial structure, including mitochondrial membranes, mitochondrial DNA (mtDNA), respiratory chain proteins, and nuclear DNA related to mitochondrial functions . SNHL occurs because of the irreversible damage to hair cells (HCs) and spiral ganglion neurons (SGNs), both of which have very limited regeneration ability in adult mice cochlea [8, 9, 10, 11, 12, 13].
Sirtuins are histone deacetylases dependent on NAD+ that remove various cellular proteins’ acyl modifications . They regulate metabolism, differentiation, stress responses, apoptosis, and the cell cycle [15, 16]. Seven members of the sirtuin family (named SIRT1–7) have been identified with different locations in the cell. Recent studies have revealed that mitochondrial sirtuins, especially SIRT3, modulate ROS levels in hearing loss pathologies and indicated that SIRT4 and SIRT5 may have a potential protective effect against hearing loss. In this review, we focus on mitochondrial dysfunction and the role of mitochondrial sirtuins in SNHL, as shown in Figures 1 and 2.
2. Hearing Loss and Mitochondrial Dysfunction
2.1. Age-Related Hearing Loss (ARHL)
ARHL, or presbycusis, is a progressive decline in hearing function that is the most prevalent type of SNHL in the elderly [17, 18, 19, 20]. It is characterized by higher hearing thresholds, beginning at high frequencies and spreading toward low frequencies, accompanied by the loss of HCs and SGNs from the basal to apical turn [21, 22, 23, 24, 25, 26]. The mechanism underlying ARHL is considered to be multifactorial, involving environmental and hereditary factors, but remains unclear. Extensive evidence suggests that mitochondria make a large contribution to the pathology of ARHL.
A previous study proposed that the accumulation of mtDNA mutations could result in age-related degenerative diseases like ARHL . Major mtDNA mutations arise in the genes encoding mitochondrial oxidative phosphorylation complexes, resulting in an impairment of its activity . Transgenic PolgA mice with knockout of the functional nuclear gene that encodes the polymerase helping repair damaged mtDNA, POLG D257A, developed hearing loss more rapidly and earlier than their wild-type counterparts. Furthermore, 10-month old PolgA mice showed severe sensorineural degeneration in the basal turn and neural degeneration in the apical turn, including clumping of surviving neurons in the cochlea . On the other hand, mtDNA mutations affect cochlear function by leading to not only mitochondrial dysfunction but also energy metabolic disturbances and induction of apoptosis .
Extensive experimental evidence indicates that oxidative stress and ROS are closely associated with the development of ARHL. A suitable model of the senescence-accelerated mouse prone 8 (SAMP8) has been established to study the impact of the aging process on various parameters. In SAMP8 mice, oxidative stress, changes in antioxidant enzyme levels, and impairment in activities of complexes I, II, and IV were shown to be involved in premature ARHL . Moreover, the level of 7,8-dihydro-8-oxoguanine, a crucial biomarker of mitochondrial and nuclear DNA damage in HCs and SGNs , increased with aging and mitochondriogenesis decreased, as assessed by the activity of citrate synthase and the ratio of mtDNA to nuclear DNA . After exposure to H2O2 (0.1 mM) for only 1 h in vitro, House Ear Institute-Organ of Corti 1 auditory cells presented with premature senescence, leading to a lower mitochondrial membrane potential (MMP), breakdown of the mitochondrial fusion/fission balance, destruction of mitochondrial morphology, and collapse of the mitochondrial network . Furthermore, oxidative stress and an accumulation of ROS increased expression of the mitochondrial proapoptotic gene Bcl-2-antagonist/killer 1 (Bak) to induce apoptosis. Suppression or deletion of Bak reduced apoptotic cell death of SGNs and HCs and prevented ARHL [34, 35].
As the major source of ROS, mitochondria contain a complex antioxidant system to resist the destructive effects of these species. Isocitrate dehydrogenase 2 (IDH2), which can convert NADP+ to NADPH, is crucial in the mitochondrial response to oxidative stress. In male mice, IDH2 deficiency accelerated the ARHL process, along with increased oxidative DNA damage and apoptosis and a loss of SGNs and HCs . Superoxide dismutase 1 (SOD1-) knockout mice also exhibited premature ARHL, characterized by an early loss of HCs, severe degeneration of SGNs, and leanness of the stria vascularis .
Glutathione peroxidase 1 (Gpx1) also has important antioxidant properties. Mice with deletion of Gpx1 showed higher hearing thresholds at high frequencies and extensive damage of HCs . Ggt1dwg/dwg mice, with deletion of the γ-glutamyl transferase 1 gene that encodes an antioxidant enzyme crucial for resynthesizing reduced glutathione (GSH), exhibited an extremely rare type of cochlear pathology in which the function of outer hair cells (OHCs) was unaffected while inner hair cells (IHCs) were unusually and selectively lost. Furthermore, treatment with N-acetyl-L-cysteine could completely prevent the hearing deficit and IHC loss in these mice . In addition, administration of EUK-207, a synthetic SOD/catalase drug, attenuated the senescence phenotype in vitro and mitigated ARHL in SAMP8 mice by increasing the expression of FOXO3A and the mRNA and protein levels of manganese SOD (Mn-SOD) and catalase .
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) could regulate mitochondrial biogenesis and upregulate the expression of oxidative stress-related genes, including Gpx1, catalase, and Mn-SOD genes [40, 41]. Overexpression of PGC-1α, with a consequent rise in nuclear respiratory factor 1 and mitochondrial transcription factor A, resulted in reduced damage to mtDNA and decreased apoptosis in the strial marginal cell aging model harboring mtDNA4834 deletion [34, 42, 43].
2.2. Noise-Induced Hearing Loss (NIHL)
Excessive exposure to noise from recreation, the environment, and various occupations can lead to hearing loss, known as NIHL, which is one of the most prevalent types of SNHL. Its typical characteristics are an increased hearing threshold, tinnitus, decreased speech discrimination score, and auditory processing disorders . Higher frequencies are preferentially affected, creating a V-shaped dip or notch, around 4 or 6 kHz . The cochlear injury following noise exposure is mainly caused by mechanical damage and biochemical pathways. Generally, OHCs are more sensitive to noise exposure than IHCs .
ROS production was observed as an early event in cochlear damage after noise exposure . As the major source of ROS, mitochondria are assumed to be damaged and, in turn, increase the accumulation of ROS. It has also been reported that mitochondrial ROS provide feedback regulation after metabolic excess, autophagy, and the inflammatory response . ROS generate lipid peroxidation products, such as 8-iso-prostaglandin F2α, that reduce blood flow in the cochlea , finally resulting in apoptosis . Ischemia may lead to cochlear hypoxia and lower adenosine triphosphate (ATP) levels and further increase the generation of ROS. On the other hand, mitochondria possess a potent antioxidant enzyme system to scavenge ROS, relying on the NADPH pool. Mn-SOD heterozygous knockout mice had worse hearing thresholds, particularly at 4 kHz, and greater damage of OHCs in all cochlear turns after noise exposure and exacerbation of NIHL . In another study, Gpx1-knockout mice exhibited greater HC and nerve fiber loss with higher auditory brainstem response thresholds .
Calcium homeostasis is also a significant factor in the occurrence and development of NIHL. After noise exposure, the level of free Ca2+increased immediately in HCs [43, 49]; the probable ion channels allowing entry are L-type Ca2+ and P2X2 ATP-gated channels . Mitochondria modulate cellular calcium homeostasis through selective calcium entry channels, the mitochondrial calcium uniporter (MCU), and the sodium-calcium exchanger with the function of extruding calcium from mitochondria . Inhibiting the MCU in CBA/J mice attenuated the loss of sensory HCs, synaptic ribbons, and the NIHL process. Furthermore, MCU-knockout mice showed resistance to noise-induced seizures and recovery of IHC synaptic connections, the auditory brainstem response, and wave I amplitude after noise exposure . Mitochondrial Ca2+ overload not only results in a decline in the MMP and overproduction of ROS but also triggers ROS-independent apoptotic and necrotic cell death pathways [50, 52, 53].
Before there is a permanent threshold shift caused by noise exposure, the level of 5-AMP-activated protein kinase (AMPK) is elevated in the spiral ligament of cochlea, in addition to an increased level of phospho-c-Jun N-terminal kinase, and this mediates the activation of apoptosis [54, 28]. Apoptosis occurs through both extrinsic and intrinsic pathways; the latter is activated by the change of mitochondrial membrane permeability. In addition to ROS, cytochrome C and caspase-independent apoptosis-inducing factor increase membrane permeability [28, 50, 55].
2.3. Ototoxic Drug-Induced Hearing Loss (ODIHL)
Platinum-based anticancer drugs, such as cisplatin, and aminoglycoside antibiotics are clinically common ototoxic drugs [56, 57, 58]. Platinum-based anticancer drugs are widely adopted to treat different kinds of cancer, and aminoglycosides are broad-spectrum antibiotics used to treat many life-threatening bacterial infections. Both can lead to hearing loss at high frequencies and preferential damage to OHCs at the cochlea basal turn [43, 59, 60–62, 63, 64].
The ototoxicity of both cisplatin and aminoglycoside antibiotics is modulated by genetic factors, and mitochondrial mutations are well-defined risk factors. Individuals bearing the mtDNA mutation A1555G in the 12S ribosomal RNA gene suffer more profound hearing loss [56, 65, 66]. C1494T is the second most common mutation identified, especially in Chinese populations [67, 68, 69]. Mutations in thiopurine S-methyltransferase (TMPT) and catechol O-methyltransferase (COMT) are related to earlier onset and greater severity of hearing loss induced by cisplatin in children . However, a more recent study revealed that variations in the TMPT or COMT genes may not correspond to cisplatin ototoxicity and did not affect hearing damage induced by cisplatin in mice. Thus, the precise role of these genes in cisplatin ototoxicity remains unclear .
Mitochondrial dysfunction and ROS are the main initiators of ODIHL. Aminoglycoside antibiotics, such as gentamicin, tend to accumulate in the mitochondria of HCs through nonselective mechanoelectrical transducer cation channels expressed on the stereociliary membranes of HCs [72–74, 75, 76]. Administration of gentamicin can directly inhibit mitochondrial protein synthesis , trigger opening of the mitochondrial permeability transition pore, and lower the MMP . Aminoglycosides can induce the release of arachidonic acid, leading to lipid peroxidation and generation of ROS [78, 79, 80, 81]. The ototoxic effect of aminoglycosides has been proposed to be linked to the formation of iron-aminoglycoside complexes that promote the formation of ROS . Downregulation of tRNA5-methylaminomethyl-2-thiouridylate methyltransferase, a mitochondrial protein, significantly made HEI-OC1 auditory cells more sensitive to damage induced by neomycin . Aminoglycosides also dysregulate calcium homeostasis, facilitating the transfer of Ca2+ into mitochondria . Elevation of mitochondrial Ca2+ levels promotes both mitochondrial oxidation and cytoplasmic ROS prior to cell death . In an in vitro study, mitochondria-specific ROS formation was evaluated in cochlear explants after exposure to gentamicin, which was accompanied by a reduction of NAD(P)H and the MMP . ROS formation in HCs in response to cisplatin leads to depletion of NADPH and binding to the sulfhydryl groups of enzymes [28, 86]. Cisplatin could stimulate the activity of NADPH oxidase 3, a relevant source of ROS, to elevate ROS levels . Oxidative stress induced by cisplatin could lead to GSH depletion, increased lipid peroxidation, and an imbalance of the oxidant/antioxidant systems .
Mitochondrial apoptotic pathways are activated following both cisplatin and aminoglycoside cochlear injury through the Bcl-2 family of proteins. After cisplatin treatment, the level of Bax was increased and the level of Bcl-2 was decreased in HCs, spiral ganglia, and the lateral wall . Pretreatment with an adenovector expressing human Bcl-2 (Ad.11D.Bcl-2) could protect HCs and preserve hearing in mice treated with gentamicin .
2.4. Inherited Hearing Loss
Sensorineural hearing loss which mainly causes by mutation of genes, known as inherited hearing loss, has been identified more common due to the development of science and technology [90, 91, 92]. Its clinical and genetical characteristics are very heterogeneous . Though the mechanism of many cases remains unclear, large evidence has proved that it has much to do with the mitochondrial function.
13 crucial polypeptides of oxidative phosphorylation were encoded by mitochondrial genome . Mutation in the mitochondria DNA has been proved to be related to the maternally inherited susceptibility in both syndromic and nonsyndromic hearing loss . Mitochondrial disorders including Kearns-Sayre syndrome, MELAS syndrome, and MERRF syndrome are always accompanied by syndromic hearing loss . In view of nonsyndromic hearing loss, extensive research has been carried out to identify the role of A1555G and C1494T mutations in 12S rRNA and emphasize the high susceptibility to hearing loss induced by drugs such as cisplatin and aminoglycoside [95, 65, 66, 96]. Mutation of 7505A>G in the tRNASer(UCN) would lead to mitochondrial dysfunction by lowering the activity of cellular respiratory chain and the level of ATP, MMP, and over produce ROS , finally induce cell apoptosis . Other variants in the tRNASer(UCN) including A7445G, T7505C, T7510C, and T7511C alter mitochondrial translation and function, involving in SNHL [95, 99, 100, 101].
The phenotypic expression of variants in mitochondrial DNA could be modulated by nuclear modifier genes, which may also play an important role in inherited hearing loss. Fan et al. had found that the interaction between p.191Gly>Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) and the 7511A>G mutation in tRNASer(UCN)caused hearing loss . Moreover, in the study of Chinese families, people who suffer both mutations present much higher penetrance of hearing loss than those who carry only one . Mtu1 is a tRNA-modifying enzyme and mtu1 knockout zebrafish exhibited a smaller number of hair cells and reductions in the hair bundle densities in the auditory and vestibular organs . Deletion of Gtpbp3 also resulted in impairment of mitochondria function in zebrafish, which provided novel opportunities for studying pathophysiology of mitochondrial disorders .
Much more mitochondrial gene loci associated with hearing loss have been discovered due to advanced technology. Mitochondrial dysfunction caused by mtDNA mutations are one of the major molecular mechanisms responsible for deafness. However, many cases remained unclear. We hope more research will be carried out in the future.
3. Sirtuins and Function
Sirtuins were originally described in yeast and named Sir2, with seven Sir2 homologs (SIRT1-7) discovered. Sirtuins consume NAD+ to deacetylate lysine residues and generate nicotinamide and 2-O-acetyl-ADP-ribose . The crucial function of sirtuins is to sense and regulate cellular metabolic responses [106, 107]. They display diverse subcellular localizations in the cell. In the nucleus, there are mainly SIRT1, SIRT6, and SIRT7, whereas in the cytoplasm, SIRT2 is located. SIRT3, SIRT4, and SIRT5 are predominantly located in the mitochondria  and are the main focus of this review. SIRT3 is the principal mitochondrial deacetylase, whereas SIRT4 and SIRT5 only have weak deacetylase functions . However, SIRT5 has robust demalonylase, desuccinylase, and deglutarylase activities , and SIRT4 can regulate lipoamidation .
SIRT3 is the main deacetylase in mitochondria, and its expression is the highest in tissues with vigorous metabolism such as the liver, kidney, and heart . SIRT3 level increases under calorie restriction, fasting, and exercise training in different tissues [112, 113]. Acetyl-CoA synthetase 2 was the first reported target of SIRT3 . However, further research revealed that SIRT3 also affected a diverse range of target proteins and participated in all major biochemical reactions and metabolic activities of mitochondria, including the respiratory chain, antioxidant defenses, and apoptosis [15, 16].
SIRT3 is an important factor involved in resisting various mitochondrial stresses, especially by utilizing cellular antioxidant systems to combat oxidative stress. SOD2, which reduces ROS levels and protects against oxidative stress, is activated by SIRT3-mediated deacetylation . SIRT3 deacetylates and activates IDH2, the major source of NADPH in mitochondria, which helps maintain GSH levels [16, 15, 116]. Deacetylation of FOXO3A, a forkhead transcription factor, by SIRT3 activates the transcription of SOD2, catalase, and other crucial antioxidant genes and protects mitochondria from further oxidative stress [117, 118]. Another key stress-sensitive pathway in mitochondria affected by SIRT3 is the mitochondrial permeability transition pore. SIRT3 deacetylates cyclophilin D  and mitochondrial fusion protein optic atrophy protein 1. These proteins affect mitochondrial dynamics and the MMP .
SIRT3 plays important roles in a wide range of diseases, including hearing loss. As mentioned above, ROS and mitochondrial dysfunction have much to do with the etiology of SNHL. SIRT3 deacetylates and activates the antioxidant system in mitochondria to reduce the level of ROS induced by noise, aging, or drugs and maintain mitochondrial permeability through deacetylation of proteins. Under caloric restriction, deacetylation and activation of IDH2 by SIRT3 increased the levels of NADPH and GSH in mitochondria, thus preventing ARHL in wild-type, but not SIRT3-knockout mice . Similarly, overexpression of SIRT3 in mice aided in preventing NIHL. Administration of the NAD+ precursor nicotinamide riboside to mice prevented the degeneration of spiral ganglia neurites and NIHL by activating the NAD+-SIRT3 pathway, and these protective effects were abrogated with SIRT3 deletion . Adjudin, a lonidamine analog, could protect cochlear HCs from gentamicin-induced damage mediated by the SIRT3-ROS axis .
SIRT4 is widely expressed and abundant in pancreatic β-cells, kidney, heart, brain, and liver [123, 110]. It has been reported that SIRT4 has no detectable NAD+-dependent deacetylase activity and function through NAD+-dependent ADP-ribosylation [16, 123]. Few studies have been carried out in other tissues, except pancreatic ß-cells, and the precise enzymatic functions of SIRT4 remain unclear. ATP is indispensable for insulin secretion by pancreatic β-cells, and SIRT4 inhibits the activity of glutamate dehydrogenase (GDH) to reduce the amount of ATP produced by the catabolism of glutamate and glutamine [124, 16]. Mice deficient in SIRT4 or subjected to calorie restriction exhibited upregulation of amino acid-stimulated insulin secretion . It is interesting that SIRT3 deacetylates and activates GDH, indicating that this enzyme may be regulated by both SIRT3 and SIRT4 [124, 125]. SIRT4 knockdown also caused increased fatty acid oxidation dependent on SIRT1, respiration, and AMPK phosphorylation .
Compared with those on SIRT3, there have been fewer studies on the regulation of SIRT4. Recent research suggests that SIRT4 may be involved in ROS homeostasis by the pyruvate dehydrogenase complex and GDH and fatty acid oxidation through malonyl-CoA decarboxylase [110, 127], ultimately reducing ROS production, that is, may have potentially optimistic effect in preservation of hearing function. However, there are studies showing that increased activity of SIRT4 may raise ROS levels in murine cardiomyocytes [128, 129]. Nevertheless, the precise mechanism of SIRT4 enzymatic activity is unknown, though it may play a role in hearing loss. Further studies are needed to identify the mechanism underlying SIRT4 function.
Unlike other sirtuins, SIRT5 primarily originated from prokaryotes , with high expression in various tissues such as the heart, brain, and liver. . The function of SIRT5 has generally become an important research topic.
SIRT5-deficient mice show no detectable alterations in the whole acetylation state of mitochondria, indicating there is a specific acetyl substrate for SIRT5 or alternative functions . And global protein hypermalonylation and hypersuccinylation are observed, indicating that SIRT5 catalyzes lysine demalonylation and desuccinylation reactions in mammals . One target of SIRT5 is carbamoyl phosphate synthetase 1 (CPS1). This enzyme has been identified as the key rate-determining step of the urea cycle for detoxification and removal of ammonia. SIRT5 upregulates CPS1 activity through deacetylation and desuccinylation, and this function is absent in SIRT5-deficient mice [124, 134, 15]. In mice overexpressing SIRT5, the CPS1 protein was more deacetylated and activated in the liver than in wild-type mice .
In terms of occurrence and development of SNHL, SIRT5 has been demonstrated to contribute to ROS homeostasis and attenuate oxidative stress. It may reduce ROS levels and oxidative stress through a mechanism similar to that of SIRT3, by deacetylation of FOXO3A and desuccinylation of IDH2, so that it may have optimistic effect on preserve hearing function [136, 137]. Another study showed that SIRT5 enhanced SOD1-mediated ROS reduction by desuccinylation . Recent evidence suggests that SIRT5 plays a potential protective role against neurodegeneration, which is a common phenomenon in SNHL. Although the mechanism remains undetermined, SIRT5 may protect neurons by limiting overproduction of ROS directly and controlling systemic ammonia levels indirectly .
Although extensive research is required to probe the pathology of hearing loss, a causative role for mitochondrial dysfunction remains one of the most solid theories. Mitochondrial sirtuins (SIRT3-5) are intimately linked to responses to stress, such as oxidative stress, metabolic regulation, and apoptosis, all of which are related to the occurrence and development of hearing loss. Moreover, we have reasons to believe SIRT3-5 have positive effect on SNHL. Moving forward, it is important to determine the precise activities of mitochondrial sirtuins as crucial targets to help prevent and cure hearing loss.
The data that support the findings of this study are openly available from the corresponding author upon reasonable request.
Conflicts of Interest
The authors declare that there is no conflict of interests regarding the publication of this paper.
We would like to thank all the authors who contributed to this special issue. This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81830030, 81771016, and 81700917).
- T. Vos, C. Allen, M. Arora et al., “Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015,” The Lancet, vol. 388, no. 10053, pp. 1545–1602, 2016.
- L. L. Cunningham and D. L. Tucci, “Hearing loss in adults,” The New England Journal of Medicine, vol. 377, no. 25, pp. 2465–2473, 2017.
- C. L. Nieman and E. S. Oh, “Hearing loss,” Annals of Internal Medicine, vol. 173, no. 11, pp. ITC81–ITC96, 2020.
- H. Zhou, X. Qian, N. Xu et al., “Disruption of Atg7-dependent autophagy causes electromotility disturbances, outer hair cell loss, and deafness in mice,” Cell Death & Disease, vol. 11, no. 10, p. 913, 2020.
- J. F. Turrens, “Mitochondrial formation of reactive oxygen species,” The Journal of Physiology, vol. 552, no. 2, pp. 335–344, 2003.
- R. S. Balaban, S. Nemoto, and T. Finkel, “Mitochondria, oxidants, and aging,” Cell, vol. 120, no. 4, pp. 483–495, 2005.
- N. D. Bonawitz, M. S. Rodeheffer, and G. S. Shadel, “Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span,” Molecular and Cellular Biology, vol. 26, no. 13, pp. 4818–4829, 2006.
- T. Wang, R. Chai, G. S. Kim et al., “Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle,” Nature Communications, vol. 6, no. 1, 2015.
- S. Zhang, Y. Zhang, Y. Dong et al., “Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea,” Cellular and Molecular Life Sciences, vol. 77, no. 7, pp. 1401–1419, 2020.
- Y. Zhang, S. Zhang, Z. Zhang et al., “Knockdown of Foxg1 in Sox9+ supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse utricle,” Aging (Albany NY), vol. 12, no. 20, pp. 19834–19851, 2020.
- S. Zhang, D. Liu, Y. Dong et al., “Frizzled-9+ supporting cells are progenitors for the generation of hair cells in the postnatal mouse cochlea,” Frontiers in Molecular Neuroscience, vol. 12, 2019.
- R. Guo, X. Ma, M. Liao et al., “Development and application of cochlear implant-based electric-acoustic stimulation of spiral ganglion neurons,” ACS Biomaterials Science & Engineering, vol. 5, no. 12, pp. 6735–6741, 2019.
- S. Zhang, R. Qiang, Y. Dong et al., “Hair cell regeneration from inner ear progenitors in the mammalian cochlea,” American Journal of Stem Cells, vol. 9, no. 3, 2020.
- A. Tuerdi, M. Kinoshita, T. Kamogashira et al., “Manganese superoxide dismutase influences the extent of noise-induced hearing loss in mice,” Neuroscience Letters, vol. 642, pp. 123–128, 2017.
- B. Osborne, N. L. Bentley, M. K. Montgomery, and N. Turner, “The role of mitochondrial sirtuins in health and disease,” Free Radical Biology & Medicine, vol. 100, pp. 164–174, 2016.
- W. He, J. C. Newman, M. Z. Wang, L. Ho, and E. Verdin, “Mitochondrial sirtuins: regulators of protein acylation and metabolism,” Trends in Endocrinology and Metabolism, vol. 23, no. 9, pp. 467–476, 2012.
- S. Someya, T. Yamasoba, R. Weindruch, T. A. Prolla, and M. Tanokura, “Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis,” Neurobiology of Aging, vol. 28, no. 10, pp. 1613–1622, 2007.
- M. Knipper, P. Van Dijk, I. Nunes, L. Rüttiger, and U. Zimmermann, “Advances in the neurobiology of hearing disorders: recent developments regarding the basis of tinnitus and hyperacusis,” Progress in Neurobiology, vol. 111, pp. 17–33, 2013.
- C. Cheng, Y. Wang, L. Guo et al., “Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea,” Stem Cell Research & Therapy, vol. 10, no. 1, p. 365, 2019.
- Z.-D. Du, S. Yu, Y. Qi et al., “NADPH oxidase inhibitor apocynin decreases mitochondrial dysfunction and apoptosis in the ventral cochlear nucleus of D-galactose-induced aging model in rats,” Neurochemistry International, vol. 124, pp. 31–40, 2019.
- E. M. Keithley, C. Canto, Q. Y. Zheng, N. Fischel-Ghodsian, and K. R. Johnson, “Age-related hearing loss and the ahl locus in mice,” Hearing Research, vol. 188, no. 1-2, pp. 21–28, 2004.
- Y. Liu, J. Qi, X. Chen et al., “Critical role of spectrin in hearing development and deafness,” Science Advances, vol. 5, no. 4, article eaav7803, 2019.
- Z.-h. He, S.-y. Zou, M. Li et al., “The nuclear transcription factor FoxG1 affects the sensitivity of mimetic aging hair cells to inflammation by regulating autophagy pathways,” Redox Biology, vol. 28, p. 101364, 2020.
- X. Fu, X. Sun, L. Zhang et al., “Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss,” The Journal of Clinical Investigation, vol. 128, no. 11, pp. 4938–4955, 2018.
- Y. Ding, W. Meng, W. Kong, Z. He, and R. Chai, “The role of FoxG1 in the inner ear,” Frontiers in Cell and Development Biology, vol. 8, article 614954, 2020.
- Z.-D. Du, S.-G. Han, T.-F. Qu et al., “Age-related insult of cochlear ribbon synapses: an early-onset contributor to D-galactose-induced aging in mice,” Neurochemistry International, vol. 133, article 104649, 2020.
- A. W. Linnane, T. Ozawa, S. Marzuki, and M. Tanaka, “Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases,” The Lancet, vol. 333, no. 8639, pp. 642–645, 1989.
- T. Kamogashira, C. Fujimoto, and T. Yamasoba, “Reactive oxygen species, apoptosis, and mitochondrial dysfunction in hearing loss,” BioMed Research International, vol. 2015, Article ID 617207, 7 pages, 2015.
- B. K. Crawley and E. M. Keithley, “Effects of mitochondrial mutations on hearing and cochlear pathology with age,” Hearing Research, vol. 280, no. 1-2, pp. 201–208, 2011.
- S. Someya, T. Yamasoba, G. C. Kujoth et al., “The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase γ,” Neurobiology of Aging, vol. 29, no. 7, pp. 1080–1092, 2008.
- J. Menardo, Y. Tang, S. Ladrech et al., “Oxidative stress, inflammation, and autophagic stress as the key mechanisms of premature age-related hearing loss in SAMP8 mouse cochlea,” Antioxidants & Redox Signaling, vol. 16, no. 3, pp. 263–274, 2012.
- S. Tanrıkulu, S. Doğru-Abbasoğlu, A. Özderya et al., “The 8-oxoguanine DNA N-glycosylase 1 (hOGG1) Ser326Cys variant affects the susceptibility to Graves' disease,” Cell Biochemistry and Function, vol. 29, no. 3, pp. 244–248, 2011.
- T. Kamogashira, K. Hayashi, C. Fujimoto, S. Iwasaki, and T. Yamasoba, “Functionally and morphologically damaged mitochondria observed in auditory cells under senescence-inducing stress,” NPJ Aging and Mechanisms of Disease, vol. 3, no. 1, p. 2, 2017.
- C. Fujimoto and T. Yamasoba, “Oxidative stresses and mitochondrial dysfunction in age-related hearing loss,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 582849, 6 pages, 2014.
- S. Someya, J. Xu, K. Kondo et al., “Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 46, pp. 19432–19437, 2009.
- K. White, M.-J. Kim, C. Han et al., “Loss of IDH2 accelerates age-related hearing loss in male mice,” Scientific Reports, vol. 8, no. 1, p. 5039, 2018.
- E. M. Keithley, C. Canto, Q. Y. Zheng, X. Wang, N. Fischel-Ghodsian, and K. R. Johnson, “Cu/Zn superoxide dismutase and age-related hearing loss,” Hearing Research, vol. 209, no. 1-2, pp. 76–85, 2005.
- D. Ding, H. Jiang, G.-D. Chen et al., “N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in γ-glutamyl transferase 1 deficient mice,” Aging (Albany NY), vol. 8, no. 4, pp. 730–750, 2016.
- N. Benkafadar, F. François, C. Affortit et al., “ROS-induced activation of DNA damage responses drives senescence-like state in postmitotic cochlear cells: implication for hearing preservation,” Molecular Neurobiology, vol. 56, no. 8, pp. 5950–5969, 2019.
- J. St-Pierre, S. Drori, M. Uldry et al., “Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators,” Cell, vol. 127, no. 2, pp. 397–408, 2006.
- P. I. Merksamer, Y. Liu, W. He, M. D. Hirschey, D. Chen, and E. Verdin, “The sirtuins, oxidative stress and aging: an emerging link,” Aging (Albany NY), vol. 5, no. 3, pp. 144–150, 2013.
- X.-Y. Zhao, J.-L. Sun, Y.-J. Hu et al., “The effect of overexpression of PGC-1α on the mtDNA4834 common deletion in a rat cochlear marginal cell senescence model,” Hearing Research, vol. 296, pp. 13–24, 2013.
- C. Fujimoto and T. Yamasoba, “Mitochondria-targeted antioxidants for treatment of hearing loss: a systematic review,” Antioxidants (Basel), vol. 8, no. 4, p. 109, 2019.
- A. R. Fetoni, F. Paciello, R. Rolesi, G. Paludetti, and D. Troiani, “Targeting dysregulation of redox homeostasis in noise-induced hearing loss: oxidative stress and ROS signaling,” Free Radical Biology & Medicine, vol. 135, pp. 46–59, 2019.
- O. S. Hong, M. J. Kerr, G. L. Poling, and S. Dhar, “Understanding and preventing noise-induced hearing loss,” Disease-a-Month, vol. 59, no. 4, pp. 110–118, 2013.
- S. M. Vlajkovic, K.-H. Lee, A. C. Y. Wong et al., “Adenosine amine congener mitigates noise-induced cochlear injury,” Purinergic Signal, vol. 6, no. 2, pp. 273–281, 2010.
- J. M. Miller, J. N. Brown, and J. Schacht, “8-iso-prostaglandin F(2alpha), a product of noise exposure, reduces inner ear blood flow,” Audiology & Neuro-Otology, vol. 8, no. 4, pp. 207–221, 2003.
- K. K. Ohlemiller, S. L. McFadden, D.-L. Ding, P. M. Lear, and Y.-S. Ho, “Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice,” Journal of the Association for Research in Otolaryngology, vol. 1, no. 3, pp. 243–254, 2000.
- A. Fridberger, A. Flock, M. Ulfendahl, and B. Flock, “Acoustic overstimulation increases outer hair cell Ca2+ concentrations and causes dynamic contractions of the hearing organ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 12, pp. 7127–7132, 1998.
- A. Kurabi, E. M. Keithley, G. D. Housley, A. F. Ryan, and A. C.-Y. Wong, “Cellular mechanisms of noise-induced hearing loss,” Hearing Research, vol. 349, pp. 129–137, 2017.
- X. Wang, Y. Zhu, H. Long et al., “Mitochondrial calcium transporters mediate sensitivity to noise-induced losses of hair cells and cochlear synapses,” Frontiers in Molecular Neuroscience, vol. 11, 2019.
- T. N. Le, L. V. Straatman, J. Lea, and B. Westerberg, “Current insights in noise-induced hearing loss: a literature review of the underlying mechanism, pathophysiology, asymmetry, and management options,” Journal of Otolaryngology - Head & Neck Surgery, vol. 46, no. 1, p. 41, 2017.
- S. Orrenius, B. Zhivotovsky, and P. Nicotera, “Regulation of cell death: the calcium-apoptosis link,” Nature Reviews. Molecular Cell Biology, vol. 4, no. 7, pp. 552–565, 2003.
- R. Nagashima, T. Yamaguchi, N. Kuramoto, and K. Ogita, “Acoustic overstimulation activates 5-AMP-activated protein kinase through a temporary decrease in ATP level in the cochlear spiral ligament prior to permanent hearing loss in mice,” Neurochemistry International, vol. 59, no. 6, pp. 812–820, 2011.
- S. W. Tait and D. R. Green, “Caspase-independent cell death: leaving the set without the final cut,” Oncogene, vol. 27, no. 50, pp. 6452–6461, 2008.
- J. Schacht, A. E. Talaska, and L. P. Rybak, “Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention,” The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, vol. 295, no. 11, pp. 1837–1850, 2012.
- H. Li, Y. Song, Z. He et al., “Meclofenamic acid reduces reactive oxygen species accumulation and apoptosis, inhibits excessive autophagy, and protects hair cell-like HEI-OC1 cells from cisplatin-induced damage,” Frontiers in Cellular Neuroscience, vol. 12, p. 139, 2018.
- W. Liu, X. Xu, Z. Fan et al., “Wnt signaling activates TP53-induced glycolysis and apoptosis regulator and protects against cisplatin-induced spiral ganglion neuron damage in the mouse cochlea,” Antioxidants & Redox Signaling, vol. 30, no. 11, pp. 1389–1410, 2019.
- M. Jiang, T. Karasawa, and P. S. Steyger, “Aminoglycoside-induced cochleotoxicity: a review,” Frontiers in Cellular Neuroscience, vol. 11, p. 308, 2017.
- Z. Zhong, X. Fu, H. Li et al., “Citicoline protects auditory hair cells against neomycin-induced damage,” Frontiers in Cell and Development Biology, vol. 8, 2020.
- S. Gao, C. Cheng, M. Wang et al., “Blebbistatin inhibits neomycin-induced apoptosis in hair cell-like HEI-OC-1 cells and in cochlear hair cells,” Frontiers in Cellular Neuroscience, vol. 13, 2020.
- Z. He, L. Guo, Y. Shu et al., “Autophagy protects auditory hair cells against neomycin-induced damage,” Autophagy, vol. 13, no. 11, pp. 1884–1904, 2017.
- Z. He, Q. Fang, H. Li et al., “The role of FOXG1 in the postnatal development and survival of mouse cochlear hair cells,” Neuropharmacology, vol. 144, pp. 43–57, 2019.
- Y. Zhang, W. Li, Z. He et al., “Pre-treatment with fasudil prevents neomycin-induced hair cell damage by reducing the accumulation of reactive oxygen species,” Frontiers in Molecular Neuroscience, vol. 12, p. 264, 2019.
- T. Nguyen and A. Jeyakumar, “Genetic susceptibility to aminoglycoside ototoxicity,” International Journal of Pediatric Otorhinolaryngology, vol. 120, pp. 15–19, 2019.
- Z. Gao, Y. Chen, and M. X. Guan, “Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity,” Journal of Otology, vol. 12, no. 1, pp. 1–8, 2017.
- H. Zhao, R. Li, Q. Wang et al., “Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family,” American Journal of Human Genetics, vol. 74, no. 1, pp. 139–152, 2004.
- D. Han, P. Dai, Q. Zhu et al., “The mitochondrial tRNAAla T5628C variant may have a modifying role in the phenotypic manifestation of the 12S rRNA C1494T mutation in a large Chinese family with hearing loss,” Biochemical and Biophysical Research Communications, vol. 357, no. 2, pp. 554–560, 2007.
- Q. Wang, Q.-Z. Li, D. Han et al., “Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss associated with the mitochondrial 12S rRNA C1494T mutation,” Biochemical and Biophysical Research Communications, vol. 340, no. 2, pp. 583–588, 2006.
- the CPNDS Consortium, C. J. D. Ross, H. Katzov-Eckert et al., “Genetic variants in TPMT and _COMT_ are associated with hearing loss in children receiving cisplatin chemotherapy,” Nature Genetics, vol. 41, no. 12, pp. 1345–1349, 2009.
- J. J. Yang, J. Y. S. Lim, J. Huang et al., “The role of inherited TPMT and COMT genetic variation in cisplatin-induced ototoxicity in children with cancer,” Clinical Pharmacology and Therapeutics, vol. 94, no. 2, pp. 252–259, 2013.
- J. Qi, L. Zhang, F. Tan et al., “Espin distribution as revealed by super-resolution microscopy of stereocilia,” American Journal of Translational Research, vol. 12, no. 1, 2020.
- J. Qi, Y. Liu, C. Chu et al., “A cytoskeleton structure revealed by super-resolution fluorescence imaging in inner ear hair cells,” Cell Discovery, vol. 5, no. 1, 2019.
- X. Yu, W. Liu, Z. Fan et al., “c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI- OC1 cells in vitro,” Scientific Reports, vol. 7, no. 1, 2017.
- A. Li, D. You, W. Li et al., “Novel compounds protect auditory hair cells against gentamycin-induced apoptosis by maintaining the expression level of H3K4me2,” Drug Delivery, vol. 25, no. 1, pp. 1033–1043, 2018.
- W. Marcotti, S. M. van Netten, and C. J. Kros, “The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels,” The Journal of Physiology, vol. 567, Part 2, no. 2, pp. 505–521, 2005.
- N. Dehne, U. Rauen, H. de Groot, and J. Lautermann, “Involvement of the mitochondrial permeability transition in gentamicin ototoxicity,” Hearing Research, vol. 169, no. 1-2, pp. 47–55, 2002.
- J. Guo, R. Chai, H. Li, and S. Sun, “Protection of hair cells from ototoxic drug-induced hearing loss,” in Advances in Experimental Medicine and Biology, vol. 1130, pp. 17–36, Springer, 2019.
- M. Guan, Q. Fang, Z. He et al., “Inhibition of ARC decreases the survival of HEI-OC-1 cells after neomycin damage in vitro,” Oncotarget, vol. 7, no. 41, pp. 66647–66659, 2016.
- Z. He, S. Sun, M. Waqas et al., “Reduced TRMU expression increases the sensitivity of hair-cell-like HEI-OC-1 cells to neomycin damage in vitro,” Scientific Reports, vol. 6, no. 1, 2016.
- S. Sun, M. Sun, Y. Zhang et al., “In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period,” Frontiers in Cellular Neuroscience, vol. 8, 2014.
- E. M. Priuska and J. Schacht, “Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex,” Biochemical Pharmacology, vol. 50, no. 11, pp. 1749–1752, 1995.
- R. Esterberg, D. W. Hailey, A. B. Coffin, D. W. Raible, and E. W. Rubel, “Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death,” The Journal of Neuroscience, vol. 33, no. 17, pp. 7513–7525, 2013.
- R. Esterberg, T. Linbo, S. B. Pickett et al., “Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death,” Journal of Clinical Investigation, vol. 126, no. 9, pp. 3556–3566, 2016.
- D. E. Desa, M. Bhanote, R. L. Hill et al., “Second-harmonic generation directionality is associated with neoadjuvant chemotherapy response in breast cancer core needle biopsies,” Journal of Biomedical Optics, vol. 24, no. 8, pp. 1–14, 2019.
- H. C. Jensen-Smith, R. Hallworth, and M. G. Nichols, “Gentamicin rapidly inhibits mitochondrial metabolism in high-frequency cochlear outer hair cells,” PLoS One, vol. 7, no. 6, article e38471, 2012.
- D. Mukherjea, S. Jajoo, T. Kaur, K. E. Sheehan, V. Ramkumar, and L. P. Rybak, “Transtympanic administration of short interfering (si)RNA for the NOX3 isoform of NADPH oxidase protects against cisplatin-induced hearing loss in the rat,” Antioxidants & Redox Signaling, vol. 13, no. 5, pp. 589–598, 2010.
- S. A. Alam, K. Ikeda, T. Oshima et al., “Cisplatin-induced apoptotic cell death in Mongolian gerbil cochlea,” Hearing Research, vol. 141, no. 1-2, pp. 28–38, 2000.
- S. C. Pfannenstiel, M. Praetorius, P. K. Plinkert, D. E. Brough, and H. Staecker, “Bcl-2 gene therapy prevents aminoglycoside-induced degeneration of auditory and vestibular hair cells,” Audiology & Neuro-Otology, vol. 14, no. 4, pp. 254–266, 2009.
- Y. Wang et al., “Loss of CIB2 causes profound hearing loss and abolishes mechanoelectrical transduction in mice,” Frontiers in Molecular Neuroscience, vol. 10, 2017.
- C. Zhu, C. Cheng, Y. Wang et al., “Loss of ARHGEF6 causes hair cell stereocilia deficits and hearing loss in mice,” Frontiers in Molecular Neuroscience, vol. 11, 2018.
- Y. He, X. Lu, F. Qian, D. Liu, R. Chai, and H. Li, “Insm1a is required for zebrafish posterior lateral line development,” Frontiers in Molecular Neuroscience, vol. 10, 2017.
- H. Kremer, “Hereditary hearing loss; about the known and the unknown,” Hearing Research, vol. 376, pp. 58–68, 2019.
- M. X. Guan, “Molecular pathogenetic mechanism of maternally inherited deafness,” Annals of the New York Academy of Sciences, vol. 1011, no. 1, pp. 259–271, 2004.
- Y. Ding, J. Leng, F. Fan, B. Xia, and P. Xu, “The role of mitochondrial DNA mutations in hearing loss,” Biochemical Genetics, vol. 51, no. 7-8, pp. 588–602, 2013.
- F. Meng, Z. He, X. Tang et al., “Contribution of the tRNAIle 4317A->G mutation to the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA 1555A->G mutation,” The Journal of Biological Chemistry, vol. 293, no. 9, pp. 3321–3334, 2018.
- L. Xue, Y. Chen, X. Tang et al., “A deafness-associated mitochondrial DNA mutation altered the tRNASer(UCN) metabolism and mitochondrial function,” Mitochondrion, vol. 46, pp. 370–379, 2019.
- F. Qian, X. Wang, Z. Yin et al., “The slc4a2b gene is required for hair cell development in zebrafish,” Aging (Albany NY), vol. 12, no. 19, pp. 18804–18821, 2020.
- X. Tang, R. Li, J. Zheng et al., “Maternally inherited hearing loss is associated with the novel mitochondrial tRNASer(UCN) 7505T>C mutation in a Han Chinese family,” Molecular Genetics and Metabolism, vol. 100, no. 1, pp. 57–64, 2010.
- R. Li, K. Ishikawa, J.-H. Deng et al., “Maternally inherited nonsyndromic hearing loss is associated with the T7511C mutation in the mitochondrial tRNASer(UCN) gene in a Japanese family,” Biochemical and Biophysical Research Communications, vol. 328, no. 1, pp. 32–37, 2005.
- V. Labay, G. Garrido, A. C. Madeo et al., “Haplogroup analysis supports a pathogenic role for the 7510T>C mutation of mitochondrial tRNA(Ser(UCN)) in sensorineural hearing loss,” Clinical Genetics, vol. 73, no. 1, pp. 50–54, 2008.
- W. Fan, J. Zheng, W. Kong et al., “Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNASer(UCN) 7511A>G mutation,” The Journal of Biological Chemistry, vol. 294, no. 50, pp. 19292–19305, 2019.
- Q. Zhang, L. Zhang, D. Chen et al., “Deletion of Mtu1 (Trmu) in zebrafish revealed the essential role of tRNA modification in mitochondrial biogenesis and hearing function,” Nucleic Acids Research, vol. 46, no. 20, pp. 10930–10945, 2018.
- D. Chen, F. Li, Q. Yang et al., “The defective expression of _gtpbp3_ related to tRNA modification alters the mitochondrial function and development of zebrafish,” The International Journal of Biochemistry & Cell Biology, vol. 77, Part A, pp. 1–9, 2016.
- J. M. Denu, “The Sir2 family of protein deacetylases,” Current Opinion in Chemical Biology, vol. 9, no. 5, pp. 431–440, 2005.
- B. Schwer and E. Verdin, “Conserved metabolic regulatory functions of sirtuins,” Cell Metabolism, vol. 7, no. 2, pp. 104–112, 2008.
- M. C. Haigis and D. A. Sinclair, “Mammalian sirtuins: biological insights and disease relevance,” Annual Review of Pathology, vol. 5, no. 1, pp. 253–295, 2010.
- E. Verdin, M. D. Hirschey, L. W. S. Finley, and M. C. Haigis, “Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling,” Trends in Biochemical Sciences, vol. 35, no. 12, pp. 669–675, 2010.
- J. Du, Y. Zhou, X. Su et al., “Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase,” Science, vol. 334, no. 6057, pp. 806–809, 2011.
- R. A. Mathias, T. M. Greco, A. Oberstein et al., “Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity,” Cell, vol. 159, no. 7, pp. 1615–1625, 2014.
- B.-H. Ahn, H.-S. Kim, S. Song et al., “A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 38, pp. 14447–14452, 2008.
- S. Someya, W. Yu, W. C. Hallows et al., “Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction,” Cell, vol. 143, no. 5, pp. 802–812, 2010.
- M. . D. Hirschey, T. Shimazu, E. Jing et al., “SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome,” Molecular Cell, vol. 44, no. 2, pp. 177–190, 2011.
- W. C. Hallows, S. Lee, and J. M. Denu, “Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 27, pp. 10230–10235, 2006.
- R. Tao, M. C. Coleman, J. D. Pennington et al., “Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress,” Molecular Cell, vol. 40, no. 6, pp. 893–904, 2010.
- W. Yu, K. E. Dittenhafer-Reed, and J. M. Denu, “SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status,” The Journal of Biological Chemistry, vol. 287, no. 17, pp. 14078–14086, 2012.
- A. H. H. Tseng, S.-S. Shieh, and D. L. Wang, “SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage,” Free Radical Biology & Medicine, vol. 63, pp. 222–234, 2013.
- C. Han and S. Someya, “Maintaining good hearing: calorie restriction, Sirt3, and glutathione,” Experimental Gerontology, vol. 48, no. 10, pp. 1091–1095, 2013.
- X. Qiu, K. Brown, M. D. Hirschey, E. Verdin, and D. Chen, “Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation,” Cell Metabolism, vol. 12, no. 6, pp. 662–667, 2010.
- S. A. Samant, H. J. Zhang, Z. Hong et al., “SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress,” Molecular and Cellular Biology, vol. 34, no. 5, pp. 807–819, 2014.
- K. . D. Brown, S. Maqsood, J.-Y. Huang et al., “Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss,” Cell Metabolism, vol. 20, no. 6, pp. 1059–1068, 2014.
- Y. Quan, L. Xia, J. Shao et al., “Adjudin protects rodent cochlear hair cells against gentamicin ototoxicity via the SIRT3-ROS pathway,” Scientific Reports, vol. 5, no. 1, 2015.
- M. C. Haigis, R. Mostoslavsky, K. M. Haigis et al., “SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells,” Cell, vol. 126, no. 5, pp. 941–954, 2006.
- D. B. Lombard, D. X. Tishkoff, and J. Bao, “Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation,” Handbook of Experimental Pharmacology, vol. 206, pp. 163–188, 2011.
- C. Schlicker, M. Gertz, P. Papatheodorou, B. Kachholz, C. F. W. Becker, and C. Steegborn, “Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5,” Journal of Molecular Biology, vol. 382, no. 3, pp. 790–801, 2008.
- N. Nasrin, X. Wu, E. Fortier et al., “SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells,” The Journal of Biological Chemistry, vol. 285, no. 42, pp. 31995–32002, 2010.
- G. Laurent, N. . J. German, A. . K. Saha et al., “SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase,” Molecular Cell, vol. 50, no. 5, pp. 686–698, 2013.
- Y.-X. Luo, X. Tang, X.-Z. An et al., “SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity,” European Heart Journal, vol. 38, no. 18, pp. 1389–1398, 2017.
- A. Lang, S. Grether-Beck, M. Singh et al., “MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4,” Aging (Albany NY), vol. 8, no. 3, pp. 484–505, 2016.
- R. A. Frye, “Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins,” Biochemical and Biophysical Research Communications, vol. 273, no. 2, pp. 793–798, 2000.
- E. Michishita, J. Y. Park, J. M. Burneskis, J. C. Barrett, and I. Horikawa, “Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins,” Molecular Biology of the Cell, vol. 16, no. 10, pp. 4623–4635, 2005.
- D. B. Lombard, F. W. Alt, H.-L. Cheng et al., “Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation,” Molecular and Cellular Biology, vol. 27, no. 24, pp. 8807–8814, 2007.
- C. Peng, Z. Lu, Z. Xie et al., “The first identification of lysine malonylation substrates and its regulatory enzyme,” Molecular & Cellular Proteomics, vol. 10, no. 12, p. M111.012658, 2011.
- T. Nakagawa, D. J. Lomb, M. C. Haigis, and L. Guarente, “SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle,” Cell, vol. 137, no. 3, pp. 560–570, 2009.
- M. Ogura, Y. Nakamura, D. Tanaka et al., “Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1,” Biochemical and Biophysical Research Communications, vol. 393, no. 1, pp. 73–78, 2010.
- L. Zhou, F. Wang, R. Sun et al., “SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense,” EMBO Reports, vol. 17, no. 6, pp. 811–822, 2016.
- Y. Wang, Y. Zhu, S. Xing, P. Ma, and D. Lin, “SIRT5 prevents cigarette smoke extract-induced apoptosis in lung epithelial cells via deacetylation of FOXO3,” Cell Stress & Chaperones, vol. 20, no. 5, pp. 805–810, 2015.
- Z.-F. Lin, H.-B. Xu, J.-Y. Wang et al., “SIRT5 desuccinylates and activates SOD1 to eliminate ROS,” Biochemical and Biophysical Research Communications, vol. 441, no. 1, pp. 191–195, 2013.
- R. A. H. van de Ven, D. Santos, and M. C. Haigis, “Mitochondrial sirtuins and molecular mechanisms of aging,” Trends in Molecular Medicine, vol. 23, no. 4, pp. 320–331, 2017.
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