Mitochondrial Fusion: The Machineries In and Out

Abstract

Mitochondria are highly dynamic organelles that constantly undergo fission and fusion. Disruption of mitochondrial dynamics undermines their function and causes several human diseases. The fusion of the outer (OMM) and inner mitochondrial membranes (IMM) is mediated by two classes of dynamin-like protein (DLP): mitofusin (MFN)/fuzzy onions 1 (Fzo1) and optic atrophy 1/mitochondria genome maintenance 1 (OPA1/Mgm1). Given the lack of structural information on these fusogens, the molecular mechanisms underlying mitochondrial fusion remain unclear, even after 20 years. Here, we review recent advances in structural studies of the mitochondrial fusion machinery, discuss their implication for DLPs, and summarize the pathogenic mechanisms of disease-causing mutations in mitochondrial fusion DLPs. The Mitochondrial Fusion MachineryMitochondria are double-membrane organelles that confer various essential cellular functions, including energy production, metabolism, apoptosis, and innate immunity [1]. They form a highly dynamic network and constantly undergo cycles of fusion and fission. The balance between fission and fusion has critical roles in maintaining mitochondrial homeostasis in response to metabolic or environmental stresses, and is linked to cell division, apoptosis, and autophagy [2-5]. In particular, fusion promotes the capacity of oxidative phosphorylation and allows redistribution of mitochondrial (mt)DNA between damaged and healthy mitochondria [6,7]. Disruptions of mitochondrial dynamics are implicated in aging as well as in several human diseases, including neurodegenerative and metabolic disorders, and cancer [8,9]. Mitochondrial fusion is a two-step process; fusion of the OMM is mediated by Fzo1 in yeast, Fzo (see Glossary) in flies, and MFN in mammals, whereas the IMM is fused by Mgm1 in yeast and OPA1 in mammals [10,11].MFN and Fzo1 were identified some 20 years ago [12][13][14][15]. Mammals have two MFNs, namely MFN1 and MFN2. Functionally, MFN1 and MFN2 share not only a certain amount of redundancy, but also substantial differences [15,16]. Mice with deletion of either MFN1 or MFN2 die in utero in mid-gestation [14]. MFN2 mutation accounts for most cases of Charcot-Marie-Tooth disease type 2A (CMT2A), a neuromuscular disorder [17]. The yeast IMM fusogen Mgm1 was initially identified as a key regulator of mtDNA maintenance [18,19]. The human OPA1 gene was mapped in genetic studies of patients with autosomal dominant optic atrophy (ADOA) [20], a hereditary neurodegenerative disease. Around the same time as the initial characterization of Fzo1 and MFNs, Mgm1 and OPA1 were annotated as membrane-bound GTPases and subsequently found to serve as IMM fusogens and cristae-shaping proteins [18,21,22]. Linkage of mitochondrial fusogen mutations to neurodegenerative diseases emphasizes the physiological importance of mitochondrial membrane dynamics in neuronal cells, likely explained by the high demand for energy there [4,8].The mechanism of mitochondrial fusion is unclear, partly due to the lack of structural in...

Cardiolipin, Non-Bilayer Structures and Mitochondrial Bioenergetics: Relevance to Cardiovascular Disease

“…It should be noted that remodeling of cristae architecture, mediated by cardiolipin along with MICOS, OPA1, and the ATP synthases, is a dynamic process that constantly involves cycles of mitochondrial membrane fusion and fission [ 111 , 112 , 113 ]. Cardiolipin is a major player supporting mitochondrial fusion.…”

“…Cardiolipin is a major player supporting mitochondrial fusion. Disruptions in the mitochondrial fusion dynamics, which are triggered by decreased levels of cardiolipin, are caused by aging and human diseases, including cardiovascular diseases [ 109 , 111 ]. In the course of over three decades of research studies on membrane fusion in model membrane systems that mimic phospholipid composition of the IMM, which were conducted by two of the three authors of this review paper, it was revealed that the membrane fusion is driven by the bilayer to non-bilayer polymorphic transitions mediated by cardiolipin in the model IMM systems [ 84 , 85 , 86 , 87 , 88 , 89 , 91 , 94 , 95 ].…”

Molecular Dysfunctions of Mitochondria‐Associated Endoplasmic Reticulum Contacts in Atherosclerosis

“…MFNs. Mitofusin (MFN), a membrane-bound dynamin-like protein named after its mitochondrial fusion activity, locating on the outer mitochondrial membrane (OMM) and mediates the merging of opposing OMMs in a GTP-dependent manner [30]. There are two types of MFNs in mammals, namely, MFN1 and MFN2, which have different roles in mediating OMM fusion.…”

Advances in the mechanism and treatment of mitochondrial quality control involved in myocardial infarction

“…Mitochondrial fusion of cardiomyocytes can be divided into two steps (Figures 2 and 3): (1) OMM fusion: when two mitochondria are in close contact, the GTP domain of Mfn binds to GTP, resulting in the conformational change of Mfn, and subsequently, GTP hydrolysis promotes the formation of Mfn dimer, thus mediating the OMM fusion; (2) IMM fusion: after OMM fusion, OPA1 forms a polymer instantaneously to induce IMM curvature, which leads to lipid fusion of two IMM to form a fusion pore, thus mediating IMM fusion, and the specific mechanism is still unclear 51 …”