Table 2 Overview of the proteins enriched at MAMs and their involvement in ALS or HMSN diseases

ER chaperones

CRT, CNX, BIP, PDI, and SIGMAR1 are enriched at MAMs⁶. They regulate ER calcium concentration (CRT and CNX) and also promote proper folding of nascent proteins in a calcium-dependent manner¹³³. When localized at MAMs, these chaperones represent high-capacity calcium stores that can be readily used when calcium needs to be transferred to the mitochondria⁶. ER chaperones can also stabilize molecular complexes: e.g. SIGMAR1 stabilizes IP3R, preventing its degradation by the proteasome⁶

Function of several ER chaperones is affected in ALS which may contribute to ER stress and motoneuron death^84,133,134

Autophagy machinery

MAMs could be an important site for autophagosome formation^93,94. Whether MAMs act as positive or negative regulators of autophagosome formation is still debated. Proteins involved in the early steps of the autophagy process, such as p150, and Vps34, as well as the autophagy-related proteins ATG15 and ATG14L, are located at the ER–mitochondria interface in conditions of starvation¹². The disruption of ER–mitochondria connections, via MFN2 or PACS-2 knockdown, prevents ATG14 enrollment and subsequent autophagosome formation in starved cells⁹⁴

Autophagy is defective in both ALS and HMSN^100,135

VAPB, MFN2, and SIGMAR1 regulate autophagy process^82,93,94 and are linked to ALS or HMSN^{34,35,36,39,42,136,137,138}

Mitochondria function, transport, and turnover

Mitochondrial fusion/fission is regulated by a pool of proteins (MFN1, MFN2, Drp1, Fis1, INF2), which participate in ER–mitochondria tethering and/or are localized at the MAMs³¹. The main mitochondrial fission protein, Drp1, forms a helix around the mitochondria to create a constriction ring

MFN2 mutations are linked to CMT2A/HMSN2A^39,42,138

ER may participate in mitochondrial fission by physically encircling the mitochondria at MAMs¹³⁹. This step relies on actin polymerization, a process which appears to be initiated by the ER factor INF2¹⁴⁰

INF2 heterozygous mutations are linked to CMT2D complicated by glomerulopathy¹⁴¹

Key regulators of mitochondrial axonal transport are also associated with the MAMs. The MIRO proteins regulate mitochondria mobility by connecting the organelles with the motor proteins kinesin and dynein. A helix–loop–helix structural domain called EF-hand motif present in the MIRO isoforms 1 and 2 functions as calcium sensor. A change in calcium level induces conformational changes in the complex, leading to the detachment of MIRO from the microtubules¹⁴²

Heterozygous missense mutations of the DNM1L gene encoding DRP1 leads to severe neonatal encephalopathy combined or not with epilepsy¹⁴³

Lipid synthesis

Enzymes involved in the synthesis of phospholipids (PS synthase 1 and 2), cholesterol, and sphingolipids (ceramide) are enriched at MAMs. Some lipids, such as PS, are transferred from the ER to the mitochondria to be transformed to PE³⁰. Mitochondrial membranes are enriched in PE, which is crucial for mitochondrial function and cell survival. The distribution of lipids in membranes forms specialized areas such as lipid rafts, and thereby modulates the recruitment of proteins at MAMs such as SIGMAR1¹⁴⁴.

The role of these factors in disease affecting motor or sensory neurons remains to be explored

Oncogenes and tumor suppressors

The tumor suppressors PML, p53, and protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN) localize to MAMs. They control ER/mitochondria calcium signalling by modulating the level of IP3R phosphorylation^27,28. At MAMs, the oncogenes HRas and KRas control calcium transfer from ER towards mitochondria and maintain calcium homeostasis during cancer progression¹⁴⁵

P53 levels are increased in ALS spinal cord motoneurons¹⁴⁶. PTEN downregulation partially protects ALS motoneurons in vitro¹⁴⁷

Inflammasome

In the inflammasome, NLRP3 serves as a platform for caspase 1 activation and maturation of pro-inflammatory cytokines such as IL1β. NLRP3 re-localizes from the ER to MAMs upon inflammation, a process that could be dependent on mitochondrial ROS production²⁹

Inflammasome components are mainly expressed in astrocytes and microglia, in the spinal cord of SOD1 ALS mice and ALS patients^148,149