Mechanistic perspective of mitochondrial fusion: Tubulation vs. fragmentation

Abstract

Mitochondrial fusion is a fundamental process driven by dynamin related GTPase proteins (DRPs), in contrast to the general SNARE-dependence of most cellular fusion events. The DRPs Mfn1/Mfn2/Fzo1 and OPA1/Mgm1 are the key effectors for fusion of the mitochondrial outer and inner membranes, respectively. In order to promote fusion, these two DRPs require post-translational modifications and proteolysis. OPA1/Mgm1 undergoes partial proteolytic processing, which results in a combination between short and long isoforms. In turn, ubiquitylation of mitofusins, after oligomerization and GTP hydrolysis, promotes and positively regulates mitochondrial fusion. In contrast, under conditions of mitochondrial dysfunction, negative regulation by proteolysis on these DRPs results in mitochondrial fragmentation. This occurs by complete processing of OPA1 and via ubiquitylation and degradation of mitofusins. Mitochondrial fragmentation contributes to the elimination of damaged mitochondria by mitophagy, and may play a protective role against Parkinson's disease. Moreover, a link of Mfn2 to Alzheimer's disease is emerging and mutations in Mfn2 or OPA1 cause Charcot-Marie-Tooth type 2A neuropathy or autosomal-dominant optic atrophy. Here, we summarize our current understanding on the molecular mechanisms promoting or inhibiting fusion of mitochondrial membranes, which is essential for cellular survival and disease control. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology.

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

“…4). A number of DLPs are involved in the fusion events within the cell (4,10,51). The molecular mechanism of membrane tethering and fusion by dynamin-related GTPases is best understood for atlastins (31,52).…”

Mitochondria dynamism: of shape, transport and cell migration

“…Fusion of the IMM is regulated by OPA1; the OPA1 gene undergoes alternative splicing producing short (s) and long (l) isoforms, both required for mitochondrial fusion [47]. The long isoform(s) is anchored to the IMM, its cleavage to the short isoform(s) being required to promote fusion of two opposing IMM, [53] but only once OM fusion has occurred.…”

“…1). Two mitofusins, MFN1 and MFN2, anchored to the OMM by transmembrane domains [46], mediate its fusion [47]. This is a multi-step process that requires mitofusins dimerization followed by their trans-association with adjacent mitochondria [48]; GTPase hydrolysis might then allow for adjacent mitochondrion membrane gathering.…”

Proteasome Impairment Induces Recovery of Mitochondrial Membrane Potential and an Alternative Pathway of Mitochondrial Fusion

“…Mitochondrial outer membrane protein Ugo1 bridges interactions between Fzo1 and Mgm1 (4)(5)(6)(7)(8). Although detailed fusion mechanisms remain to be solved, the ubiquitin-proteasome system has been suggested to regulate mitochondrial dynamics.…”