Oxidative Medicine and Cellular Longevity

Research Article

Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Prospective Roles in Kidney Disease

Table 2

Summary of the functional roles of MAMs-resident proteins listed in this text.


Proteins	Relevant function(s) in MAMs	Expression in human kidney
Proteins	Relevant function(s) in MAMs	Glomeruli	Tubules

(1) Protethering proteins
PACS2	Regulation of apoptosis, ER homeostasis, Ca²⁺ between mitochondria and ER [15], and mitophagosome formation [104]	Low	Low
Grp75	Cytosolic molecular chaperone that links ER-resident IP3Rs to OMM-resident VDACs, resulting in increased MAMs formation and enhanced mitochondria Ca²⁺ uptake [25]	~High	High
IP3Rs	Interaction with Grp75 and VDACs, forming an intracellular calcium regulation axis in MAMs [25]	~medium	High
VDACs	Interaction with Grp75 and IP3Rs, forming an intracellular Ca²⁺ regulation axis in MAMs [25]	~high	High
Mfn2	Major modulator of ER-mitochondria tethering and mitochondrial fusion [26], but its role in organelle tethering is actually highly controversial, regardless of which tissue is considered. For a detailed discussion, please see the recent review in [157]	~Low	High
Mfn1	Tethering mitochondria to MAMs via interaction with ER-resident Mfn2 [26].	~Low	High
Fis1	Regulator of ER-mitochondria tethering via interaction with BAP31 and establishing a platform for apoptosis induction [27]. Fis1 dynamically regulates STX17 distribution at MAMs microdomains and induces Parkin-independent mitophagy [158]	High	High
BAP31	Interaction with TOM40 within MAMs and regulating mitochondrial function [159], as an interacting partner of CDIP1 and establishes an ER-mitochondrial crosstalk for ER stress-mediated apoptosis signaling [160]	~Medium	Medium~high
VAPB	Interacts with PTPIP51 to form a tethering complex [28, 29] and regulates autophagy by facilitating ER-mitochondria Ca²⁺ exchange [29]	Medium~high	Medium~high
PTPIP51	Interacts with the ER-resident protein VAPB to regulate ER-mitochondria associations and cellular Ca²⁺ homeostasis [28]. Interacting with ORP5/8 within MAMs to modulate mitochondrial morphology and function [161]	Medium	High
BECN1	Relocalization to the MAMs compartment in a Pink1-dependent manner and thereby enhances the formation of MAMs and autophagosomes [13]	Medium	Medium
FUNDC1	Localized to MAMs by binding to calnexin, where it promotes Drp1-dependent mitochondrial fission and mitophagy [162]. Additionally, binding of FUNDC1 to IP3R2 at the MAMs also increases the Ca²⁺ concentration in both the cytosol and the mitochondrial matrix, therefor promoting Fis1-dependent mitochondrial fission and mitophagy [30]	Low	Medium
PDZD8	Necessary for the formation of MAMs and required for mitochondrial Ca²⁺ uptake [31]	Medium	Medium
MITOL	Regulates mitochondrial dynamics and MAMs formation in a Mfn2-dependent manner [33] and maintains ER-mitochondria phospholipids transfer, such as in cardiolipin biogenesis [163]	NA	NA
Parkin	The role of Parkin in maintaining MAMs integrity is controversial. Some research indicates that Parkin tethers mitochondria to the ER by ubiquitination of Mfn2 [94, 95], while other results suggest that Parkin-mediated ubiquitination coupled to Pink1-catalyzed phosphorylation of Mfn2 dissociates mitochondria from the ER [164]	Medium	High

(2) IP3Rs/Grp75/VDAC complex-modulated proteins
Sig-1R	Interacts with BiP and prolongs Ca²⁺ signaling from the ER into mitochondria by stabilizing IP3R3 at MAMs; increased Sig-1R in cells counteracts the ER stress response, whereas decreased Sig-1R enhances apoptosis [34]	~Low	Low~medium
CypD	Interacts with the VDAC1/Grp75/IP3R1 complex within MAMs and controls the Ca²⁺ transfer from the ER to mitochondria through IP3R1 [35]	NA	NA
Tespa1	Involved in maintaining MAMs integrity and functions as a regulator of mitochondrial Ca²⁺ flux from ER through the physical association with IP3R3 and GRP75, but not with VDAC1 [36]	Not detected	Medium
RTN-1C	Involved in maintaining MAMs integrity by binding to VDAC and FACL4 and affects mitochondrial morphology, Ca²⁺ responses, and lipid exchange with the ER [37]	Not detected	Not detected
GSK3β	GSK3β specifically interacts with the IP3R1/Grp75/VDAC1 complex in MAMs, and inhibition of GSK3β reduced both IP3R1 phosphorylation and ER Ca²⁺ release, which consequently diminishes both cytosolic and mitochondrial Ca²⁺ concentrations, as well as sensitivity to apoptosis [38]	~Low	~Medium
DISC1	Interacts with IP3R1 at MAMs and downregulates its ligand binding, thereby reducing the ER-mitochondria Ca²⁺ transfer [39]	Not detected	Medium
TOM70	Clusters at ER-mitochondria contacts, recruits IP3R3, and promotes ER to mitochondria Ca²⁺ transfer, bioenergetics, and cell proliferation [40]	Low	Medium
TGM2	TGM2 interacts with Grp75 within MAMs and regulates the interaction between IP3R3 and Grp75; the resulting association controls ER-mitochondrial Ca²⁺ flux and the profile of the MAMs proteome [41]	Medium	Medium
WFS1	Binds to NCS1 to form a complex with IP3R1 to activate ER-mitochondria Ca²⁺ crosstalk to promote mitochondrial function, i.e., activation of the TCA cycle and mitochondrial respiratory chain [42]	Low	High
PDK4	Moderates Ca²⁺ transfer from ER to mitochondria by interacting with and stabilizing the IP3R1-Grp75-VDAC1 complex at the MAMs\ interface and consequently maintains mitochondrial function [43]	Low	High
EI24	Tethering ER to mitochondria through forming a quaternary complex with IP3R1/Grp75/VDAC1 and regulating autophagy flux [44]	Medium	Medium

(3) Antitethering proteins
TpMs	The expression of TpMs leads to mitochondrial fragmentation and loosens tethering with ER in a Mfn2-dependent manner [45]	Low	Medium
FATE1	Acts as a negative regulator of MAMs via interacting with the ER chaperones and emerin (EMD) and the mitochondrial protein Mic60/mitofilin and antagonizes calcium-induced apoptosis by uncoupling ER and mitochondria [46]	Not detected	Not detected
CAV1	Negatively regulates the formation of MAMs and therefore impairs Ca²⁺ transfer via the MAMs platform and compensatory mitochondrial bioenergetics response to early ER stress [47]; contrary results regarding the role of CAV1 in MAMs integrity were concluded by ref. [21].	Medium	Not detected

(4) Upstream regulators of the formation of MAMs
GSK3β	Serves as a regulator of MAMs formation by regulating the VAPB–PTPIP51 interaction [28].	~Low	~Medium
p38 MAPK	Phosphorylation of Gp78 at S538 by p38 MAPK inhibits MAMs formation and mitochondrial fusion by promoting degradation of Mfn1/2 [48]	Not detected	Medium
PKG	Involved in the regulation of MAMs integrity [49]	Medium	Low
FOXO1	Augments MAMs formation via induction of PDK4 overexpression and promotes mitochondrial Ca²⁺ accumulation, mitochondrial dysfunction, and ER stress [43]	Low	Low
PKA	Phosphorylation and alterations in organelle distribution of the Drp1, thereby enhancing ER-mitochondria communication [47]	~Medium	Medium~high
AMPKα	Activation of AMPK suppresses the formation and function of MAMs by reducing the transcription of FUNDC1 [50]. AMPK binds directly to the MAMs tether Mfn2 and are therefore involved in MAMs formation [32]	Low	Medium

Note. These data were freely obtained from the Human Protein Atlas (http://www.proteinatlas.org) based on immunohistochemistry staining in normal human kidney samples. Abbreviations: NA: not applicable; STX17: Syntaxin 17; CDIP1: cell death-inducing p53 target 1; ORP5/8: oxysterol-binding protein-related proteins 5/8; BiP: 78 KDa glucose-regulated protein; NCS1: neuronal calcium sensor 1; Gp78: autocrine motility factor receptor; TCA cycle: tricarboxylic acid cycle.