Mitochondrial GTPase mitofusin 2 mutation in Charcot?Marie?Tooth neuropathy type 2A

185

153

Background: Mitofusin 2 is a mitochondrial outer membrane protein with multiple functions. Results: Mitofusin 2 deficiency in the heart causes autophagosomes to accumulate and leads to cardiac dysfunction. Conclusion: Mitofusin 2 serves as an adaptor protein to mediate the fusion of autophagosomes with lysosomes in the heart. Significance: Mitofusin 2 has a novel and essential role in cardiac autophagic regulation.

mentioning

confidence: 99%

Central Role of Mitofusin 2 in Autophagosome-Lysosome Fusion in Cardiomyocytes

Zhao

Huang

Han

et al. 2012

185

153

“…Notably, mutations in genes controlling mitochondrial fusion have been directly associated with several human diseases. Mutations in Mfn2 were found in patients with Charcot-Marie-Tooth neuropathy type 2A (27,28), and mutations in the OPA1 gene have been shown to cause dominant optic atrophy (29,30). Thus, defects in mitochondrial fusion cause cellular dysfunctions that relate to different human diseases.…”

mentioning

confidence: 99%

Mitochondrial Fission and Fusion Mediators, hFis1 and OPA1, Modulate Cellular Senescence

Lee

Jeong

Lim

et al. 2007

257

187

The number and morphology of mitochondria within a cell are precisely regulated by the mitochondrial fission and fusion machinery. The human protein, hFis1, participates in mitochondrial fission by recruiting the Drp1 into the mitochondria. Using short hairpin RNA, we reduced the expression levels of hFis1 in mammalian cells. Cells lacking hFis1 showed sustained elongation of mitochondria and underwent significant cellular morphological changes, including enlargement, flattening, and increased cellular granularity. In these cells, staining for acidic senescence-associated ␤-galactosidase activity was elevated, and the rate of cell proliferation was greatly reduced, indicating that cells lacking hFis1 undergo senescence-associated phenotypic changes. Reintroduction of the hFis1 gene into hFis1-depleted cells restored mitochondrial fragmentation and suppressed senescence-associated ␤-galactosidase activity. Moreover, depletion of both hFis1 and OPA1, a critical component of mitochondrial fusion, resulted in extensive mitochondrial fragmentation and markedly rescued cells from senescence-associated phenotypic changes. Intriguingly, sustained elongation of mitochondria was associated with decreased mitochondrial membrane potential, increased reactive oxygen species production, and DNA damage. The data indicate that sustained mitochondrial elongation induces senescence-associated phenotypic changes that can be neutralized by mitochondrial fragmentation. Thus, one of the key functions of mitochondrial fission might be prevention of the sustained extensive mitochondrial elongation that triggers cellular senescence.Mitochondria are dynamic organelles that can change in number and morphology within a cell during development, the cell cycle, or when challenged with various cytotoxic conditions. Size, shape, and interconnectivity of mitochondria are determined by fusion and fission. In mammals, the key molecules for mitochondrial fission are hFis1 and Drp1. The hFis1 protein is anchored to the outer mitochondrial membrane via a C-terminal transmembrane domain, and overexpression of hFis1 was found to induce mitochondrial fragmentation (1, 2). The Drp1 is predominantly distributed in the cytoplasm and partially associates with the mitochondrial outer membrane (3). A portion of cytosolic Drp1 can be recruited to mitochondria through an interaction with hFis1 (4 -6). The opposing process, mitochondrial fusion, is controlled in mammalian cells by Mitofusins (Mfn) 3 and OPA1. Mitofusin1 and -2 (Mfn1 and Mfn2) localize on the outer membrane of mitochondria and may directly mediate mitochondrial fusion (7-9). OPA1 (optic atrophy 1) is a dynamin family GTPase that resides in the intermembrane space of mitochondria and is essential for mitochondrial fusion (10, 11). However, the functional mechanism by which these proteins cooperate to induce mitochondrial fission and fusion remains unidentified.Despite relatively intensive studies on the components of the mitochondrial fission and fusion machineries, a link between mitochondrial...

“…Fragmentation leads to a loss of mtDNA and respiratory incompetence in yeast (1,2) and accumulation of poorly functional mitochondria in mammals (3). Mice deficient for mitochondrial fusion die during mid gestation (4), and mutations in the mitochondrial fusion genes Mfn2 and OPA1 cause the neurodegenerative diseases Charcot-Marie-Tooth disease type 2A and dominant optic atrophy, respectively (5)(6)(7)(8)(9). Importantly, the mitochondrial fusion machinery is dedicated solely to mitochondrial fusion and does not include SNARE 2 proteins or NSF (N-ethylmaleimide-sensitive protein), which mediate most other intracellular membrane fusion events.…”

mentioning

confidence: 99%

Domain Interactions within Fzo1 Oligomers Are Essential for Mitochondrial Fusion

Griffin

Chan

2006

Mitofusins are conserved GTPases essential for the fusion of mitochondria. These mitochondrial outer membrane proteins contain a GTPase domain and two or three regions with hydrophobic heptad repeats, but little is known about how these domains interact to mediate mitochondrial fusion. To address this issue, we have analyzed the yeast mitofusin Fzo1p and find that mutation of any of the three heptad repeat regions (HRN, HR1, and HR2) leads to a null allele. Specific pairs of null alleles show robust complementation, indicating that functional domains need not exist on the same molecule. Biochemical analysis indicates that this complementation is due to Fzo1p oligomerization mediated by multiple domain interactions. Moreover, we find that two non-overlapping protein fragments, one consisting of HRN/GTPase and the other consisting of HR1/HR2, can form a complex that reconstitutes Fzo1p fusion activity. Each of the null alleles disrupts the interaction of these two fragments, suggesting that we have identified a key interaction involving the GTPase domain and heptad repeats essential for fusion.The balance between fusion and fission maintains mitochondria as a dynamic tubular reticulum. In the absence of fusion, ongoing fission results in complete fragmentation of the mitochondrial network. Fragmentation leads to a loss of mtDNA and respiratory incompetence in yeast (1, 2) and accumulation of poorly functional mitochondria in mammals (3). Mice deficient for mitochondrial fusion die during mid gestation (4), and mutations in the mitochondrial fusion genes Mfn2 and OPA1 cause the neurodegenerative diseases Charcot-Marie-Tooth disease type 2A and dominant optic atrophy, respectively (5-9). Importantly, the mitochondrial fusion machinery is dedicated solely to mitochondrial fusion and does not include SNARE 2 proteins or NSF (N-ethylmaleimide-sensitive protein), which mediate most other intracellular membrane fusion events. Thus, mitochondrial fusion likely involves a unique mechanism.There are three essential components of the fusion pathway in yeast. The yeast mitofusin Fzo1p is a 98-kDa transmembrane GTPase uniformly distributed in the mitochondria outer membrane (1, 2). Both the N-and C-terminal portions of Fzo1p are oriented toward the cytosol, in position to mediate important steps during fusion (1, 2). Mgm1p is a dynamin-related protein in the mitochondrial intermembrane space (10 -12). It remains unclear if Mgm1p possesses the membrane severing activity of other dynamin family members, and if so, how this activity relates to its requirement for fusion. The third component of the fusion pathway is Ugo1p, a 58-kDa protein that spans the outer membrane once and interacts with both Fzo1p and Mgm1p (10,[12][13][14]. In this capacity, Ugo1p may anchor a fusion complex that coordinates the mitochondrial outer and inner membranes during fusion.Fzo1p is the best candidate to directly mediate fusion of the mitochondrial outer membrane. Unlike Mgm1p, it is positioned in the outer membrane and unlike Ugo1p its requisite ro...