The Molecular Determinants of Mitochondrial Membrane Contact With ER, Lysosomes and Peroxisomes in Neuronal Physiology and Pathology

Abstract

Membrane tethering is an important communication method for membrane-packaged organelles. Mitochondria are organelles with a bilayer membrane, and the membrane contact between mitochondria and other organelles is indispensable for maintaining cellular homeostasis. Increased levels of molecular determinants that mediate the membrane contact between mitochondria and other organelles, and their functions, have been revealed in recent years. In this review article, we aim to summarize the findings on the tethering between mitochondria and other organelles in physiological or pathological conditions, and discuss their roles in cellular homeostasis, neural activity, and neurodegenerative diseases.

Keywords: determinant; membrane contact; mitochondria; neurological diseases; pathological condition; physiological condition.

Figure 1

Paradigm of molecular determinants in endoplasmic reticulum (ER)-mitochondria tethering in yeast. Mdm10, Mdm34 and Gem1 located at the outer mitochondrial membrane (OMM) mediate ER-mitochondria tethering by forming a complex with ER membrane located proteins Mmm1 and cytosol Mdm12 in yeast. ER membrane protein complex (EMC) mediates ER-mitochondria contact by interacting with TOM5 at the mitochondrial OMM in yeast. Mdm10/34, mitochondrial distribution and morphology protein 10/34; Gem1, mitochondrial Rho GTPase 1; TOM5, translocase of outer membrane 5 kDa subunit.

Figure 2

Paradigm of molecular determinants in ER-mitochondria tethering in mammal. Left: GRP75 interacts with both VDAC (located at OMM) and IP₃R3 (located at MAM) to form a complex that mediates the ER-mitochondria contact. The interaction between Sig-1R and IP₃R3 promotes the stability of IP₃R3, which is essential for the IP₃R3-GRP75-VDAC complex, while BiP inhibits this interaction by competitive binding to Sig-1R. Middle: MFN1/2 form a dimer at MAM and mediate ER-mitochondria tethering. PARKIN, PINK1 and MITOL mediate the mono-ubiquitination of MFN2 and promote MFN2 translocation to MAM. However, the poly-ubiquitination of MFN2 mediated via PARKIN and PINK1 leads to the tethering disruption. Right: Miro1/2 form a cluster at MAM and mediate ER-mitochondria tethering, and the phosphorylation of Miro2 by polo kinase is essential for the formation of the Miro cluster. Cytosolic PACS2 recruits to the MAMs and OMM to mediate ER-mitochondria membrane contact. The OMM-resident PTPIP51 interacts with ORP5/8 at MAM to maintain mitochondrial morphology and respiratory functions. The OMM-resident PIGBOS interacts with the ER membrane protein CLCC1 to maintain ER–mitochondrial contact. GRP75, 75 kDa glucose-regulated protein; VDAC1/2, voltage-dependent anion-selective channel protein; IP₃R3, inositol 1,4,5-trisphosphate receptor type 3; MFN1/2, mitofusin-1/2; Sig-1R, sigma-1 receptor; ORP5/8, oxysterol-binding protein (OSBP)-related proteins 5/8; PTPIP51, protein tyrosine phosphatase interacting protein-51; CLCC1, chloride channel CLIC-like protein 1; PIGBOS, PIGB opposite strand 1; PACS2, phosphofurin acidic cluster sorting protein 2; Miro1/2, mitochondrial Rho 1/2; MITOL: mitochondrial ubiquitin ligase; PINK1, PTEN-induced putative kinase protein 1.

Figure 3

Paradigm of molecular determinants in ER-mitochondria tethering in the dendrite of neurons. In the dendrite, VAPB (located at ER) interacts with PTPIP51 (located at OMM) to maintain ER–mitochondria tethering and synaptic activity-coupled Ca²⁺ release-uptake. PDZD8 (located at ER) and Rmdn3 (located at OMM) are also involved in synaptic activity-coupled Ca²⁺ release-uptake and ER-mitochondria membrane contact. However, their interacting partners have still not been identified. VAPB, vesicle-associated membrane protein-associated protein B; PDZD8, PDZ domain-containing protein 8; Rmdn3, regulator of microtubule dynamics protein 3.

Figure 4

Paradigm of changes in molecular determinants and ER-mitochondria tethering in neurodegenerative disorders. Upper: the absence of Sig-1R at MAM leads to the de-stabilization of IP₃R3, resulting in the decreased IP₃R3-GRP75-VDAC complex and ER-mitochondria tethering, which is associated with the development of amyotrophic lateral sclerosis (ALS). SNCA, FUS and TDP43 disrupt the VAPB-PIPTP51 interaction and ER–mitochondria contact, which is associated with the development of Parkinson’s disease (PD) and ALS. Bottom: the accumulation of Aβ at MAM promotes the expression of VDAC and IP₃R3, which leads to the increased formation of the IP₃R3-GRP75-VDAC complex, ER-mitochondria tethering, and mitochondrial Ca²⁺ overload. APP-C99 is also observed at MAMs, which enhances the ER-mitochondrial contact. The presence of Aβ and APP-C99 at MAMs are associated with the development of Alzheimer’s disease (AD). SNCA, synuclein-α; TDP43, TAR DNA-binding protein 43; FUS, RNA-binding protein FUS; Aβ, β amyloid.