Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics

Abstract

Mitochondrial quality control is fundamental to all neurodegenerative diseases, including the most prominent ones, Alzheimer’s Disease and Parkinsonism. It is accomplished by mitochondrial network dynamics – continuous fission and fusion of mitochondria. Mitochondrial fission is facilitated by DRP1, while MFN1 and MFN2 on the mitochondrial outer membrane and OPA1 on the mitochondrial inner membrane are essential for mitochondrial fusion. Mitochondrial network dynamics are regulated in highly sophisticated ways by various different posttranslational modifications, such as phosphorylation, ubiquitination, and proteolytic processing of their key-proteins. By this, mitochondria process a wide range of different intracellular and extracellular parameters in order to adapt mitochondrial function to actual energetic and metabolic demands of the host cell, attenuate mitochondrial damage, recycle dysfunctional mitochondria via the mitochondrial autophagy pathway, or arrange for the recycling of the complete host cell by apoptosis. Most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases. Mutations in one of these genes are associated with a neurodegenerative disease that originally was described to affect retinal ganglion cells only. Since more and more evidence shows that other cell types are affected as well, we would like to discuss the pathology of dominant optic atrophy, which is caused by heterozygous sequence variants in OPA1, in the light of the current view on OPA1 protein function in mitochondrial quality control, in particular on its function in mitochondrial fusion and cytochrome C release. We think OPA1 is a good example to understand the molecular basis for mitochondrial network dynamics.

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

“…15 However, NDPK-D interacts not only with CL, 14 but also with OPA1, 7 a dynamin-like GTPase. OPA1, beyond its classical role in inner membrane fusion, 41,42 is also directly implicated in mitochondrial quality control via its stressregulated proteolytic cleavage via OMA1. 25,26,43 In functional mitochondria, OPA1/NDPK-D interaction helps to fuel OPA1 with GTP, 44 but this topology has to be different from the one where NDPK-D is cross-linking the two mitochondrial membranes, which is kinase inactive.…”

Axon Transport and Neuropathy

“…OPA1 is a dynamin-like membrane scission GTPase protein present in the mitochondrial membrane with a critical function in mitochondrial membrane fusion. 56 Altered mitochondrial dynamics and respiration associated with OPA1 mutations likely result in neuropathy, and, although many mutations appear to result in loss of protein function, it is not clear how they specifically lead to axon degeneration.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Moreover, Opa-1 is a regulator of the mitochondrial quality control. Indeed, reduction in mitochondrial membrane potential (Δy) stimulates an imbalance toward the Opa-1-S isoform, thus inhibiting mitochondrial fusion and allowing damaged mitochondria to be degraded through mitophagy [14]. Fusion of the mitochondrial network is also very important for regulating the mixing of mtDNA among these organelles [15].…”