Mitochondrial Fusion Protects against Neurodegeneration in the Cerebellum

Chen, Hsiuchen; McCaffery, J. Michael; Chan, David C.

doi:10.1016/j.cell.2007.06.026

Cited by 792 publications

(756 citation statements)

References 43 publications

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“…Mfn1‐adKO and Mfn2‐adKO mice were generated by crossing Mfn1 loxP/loxP or Mfn2 loxP/loxP mice (Chen et al , 2007) backcrossed to a C57BL/6 background, with mice expressing the Cre recombinase under the adiponectin promoter (adipoQ‐Cre mice). In the article, Mfn2 loxP/loxP and Mfn2 loxP/loxP ‐adipoQ CRE/− mice will be respectively called control and Mfn2‐adKO.…”

Section: Methodsmentioning

confidence: 99%

Mfn2 is critical for brown adipose tissue thermogenic function

et al. 2017

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Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine‐tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin‐resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose‐specific Mfn2 knockout (Mfn2‐adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2‐adKO mice were protected from high‐fat diet‐induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole‐body energy homeostasis.

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Section: Methodsmentioning

confidence: 99%

Mfn2 is critical for brown adipose tissue thermogenic function

et al. 2017

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“…Mutations in the MFN2 and OPA1 genes are associated with neurodegenerative diseases-Charcot-Marie-Tooth neuropathy type 2A (CMT2A) and dominant optic atrophy (OA), respectively (10)(11)(12). Neurodegeneration appears to be the prominent phenotype in mice with a targeted mutation in MFN2, and cells lacking mitochondrial fusion show a severe defect in their respiratory capacity (13,14). Particularly, fusion events allow efficient complementation of damaged proteins, DNA and RNA.…”

Section: Mitochondrial Dynamics In Neuronsmentioning

confidence: 99%

“…The mixing of the matrix content of a few damaged mitochondria with the larger matrix pool of the intact mitochondrial network potentially allows an efficient complementation of biomolecules (26). Therefore, effective mitochondrial ''content mixing'' is able to reduce the deleterious effects of damaged proteins and RNAs and mutated mitochondrial DNAs (mtDNAs) (13,14,25). In this aspect, the correct function of mitochondrial quality control and mitochondrial dynamics appear very much interrelated.…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

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The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013

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“…Strikingly, most recent studies reveal that abnormal mitochondrial fusion and fission participate in the regulation of apoptosis 5,6 . In particular, they are related to a variety of diseases such as skeletal muscle disorders [7][8][9] , peripheral neuropathy CharcotMarie-Tooth type 2A 10,11 and neurodegeneration 12 .…”

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confidence: 99%

miR-484 regulates mitochondrial network through targeting Fis1

et al. 2012

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mitochondria constantly undergo fusion and fission, two necessary processes for the maintenance of organelle fidelity. The abnormal mitochondrial fission participates in the pathogenesis of many diseases, but its regulation remains poorly understood. Here we show that miR-484 can suppress translation of mitochondrial fission protein Fis1, and inhibit Fis1-mediated fission and apoptosis in cardiomyocytes and in the adrenocortical cancer cells. We demonstrate that Fis1 is necessary for mitochondrial fission and apoptosis, and is upregulated during anoxia, whereas miR-484 is downregulated. miR-484 is able to attenuate Fis1 upregulation and mitochondrial fission, by binding to the amino acid coding sequence of Fis1 and inhibiting its translation. In exploring the underlying mechanism of miR-484 downregulation upon apoptosis, we observe that Foxo3a transactivates miR-484 expression. Foxo3a transgenic or knockout mice exhibit, respectively, a high or low level of miR-484 and a reduced or enhanced mitochondrial fission, apoptosis and myocardial infarction. our data reveal a model of mitochondrial fission regulation by a microRnA.

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Mitochondrial Fusion Protects against Neurodegeneration in the Cerebellum

Cited by 792 publications

References 43 publications

Mfn2 is critical for brown adipose tissue thermogenic function

Mfn2 is critical for brown adipose tissue thermogenic function

Mitochondrial involvement in neurodegenerative diseases

miR-484 regulates mitochondrial network through targeting Fis1

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