Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA Mutations

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Cell (Impact Factor: 32.24). 04/2010; 141(2):280-9. DOI: 10.1016/j.cell.2010.02.026
Source: PubMed


Mitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange contents, including mitochondrial DNA (mtDNA). Here we examine the functions of mitochondrial fusion in differentiated skeletal muscle through conditional deletion of the mitofusins Mfn1 and Mfn2, mitochondrial GTPases essential for fusion. Loss of the mitofusins causes severe mitochondrial dysfunction, compensatory mitochondrial proliferation, and muscle atrophy. Mutant mice have severe mtDNA depletion in muscle that precedes physiological abnormalities. Moreover, the mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of mitochondrial fusion strongly increases mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, mitochondrial fusion is likely to be a protective factor in human disorders associated with mtDNA mutations.

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    • "On the other hand more time consuming states of fusion of mitochondria have been found to not only include the outer membrane but also the inner membrane and mitochondrial matrix components.[20]In these fusion states mitochondria are considered to share and compensate for defect protein complexes or DNA sequences which are crucial for the production of ATP.[28]Subsequent fission events lead to one mitochondrium with a still polarized MMP and one mitochondrium with a depolarized MMP.[21]Considering the two different types of connections among mitochondria we decided to separate the biophysical definition for fission and fusion processes in the model into two parts: metabolic fission and fusionwhere γ denotes a constant to balance both kinds of fission and fusion relatively to each other. Metabolic fission and fusion. "
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    ABSTRACT: Mitochondria are essential for the energy production of eukaryotic cells. During aging mitochondria run through various processes which change their quality in terms of activity, health and metabolic supply. In recent years, many of these processes such as fission and fusion of mitochondria, mitophagy, mitochondrial biogenesis and energy consumption have been subject of research. Based on numerous experimental insights, it was possible to qualify mitochondrial behaviour in computational simulations. Here, we present a new biophysical model based on the approach of Figge et al. in 2012. We introduce exponential decay and growth laws for each mitochondrial process to derive its time-dependent probability during the aging of cells. All mitochondrial processes of the original model are mathematically and biophysically redefined and additional processes are implemented: Mitochondrial fission and fusion is separated into a metabolic outer-membrane part and a protein-related inner-membrane part, a quality-dependent threshold for mitophagy and mitochondrial biogenesis is introduced and processes for activity-dependent internal oxidative stress as well as mitochondrial repair mechanisms are newly included. Our findings reveal a decrease of mitochondrial quality and a fragmentation of the mitochondrial network during aging. Additionally, the model discloses a quality increasing mechanism due to the interplay of the mitophagy and biogenesis cycle and the fission and fusion cycle of mitochondria. It is revealed that decreased mitochondrial repair can be a quality saving process in aged cells. Furthermore, the model finds strategies to sustain the quality of the mitochondrial network in cells with high production rates of reactive oxygen species due to large energy demands. Hence, the model adds new insights to biophysical mechanisms of mitochondrial aging and provides novel understandings of the interdependency of mitochondrial processes.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "Indeed, they showed that increasing the expression of the mitochondrial fission machinery (Drp1 and FIS1 over-expression) triggers skeletal muscle atrophy, while inhibiting mitochondrial fission partly prevented the muscle atrophy triggered by FOXO3 over-expression (Romanello et al. 2010). By studying mice lacking mitofusin 1 and 2 function in skeletal muscle, Chen et al. showed that mitochondrial fusion is required to maintain the integrity of mitochondrial DNA, for normal mitochondrial function, and for normal muscle growth and development (Chen et al. 2010). Two recent articles published in The Journal of Physiology by Cannavino and colleagues (Cannavino et al. 2014, 2015) further increased our understanding of the role played by mitochondrial dynamics in muscle physiology and in the regulation of muscle mass. "

    Full-text · Article · Jul 2015 · The Journal of Physiology
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    • "These processes, termed mitochondrial dynamics, are important for maintenance of functional mitochondria. Mitochondrial fusion is regulated by mitofusin proteins (Mfn1 and Mfn2) and optic atrophy 1 (Opa1) in the outer and inner mitochondrial membranes , respectively (Meeusen et al. 2006; Chen et al. 2010). Opa1 undergoes proteolytic processing, which has been shown to be essential for fusion activity (Duvezin-Caubet et al. 2006; Wang et al. 2014). "
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    ABSTRACT: It is well known that resistance exercise increases muscle protein synthesis and muscle strength. However, little is known about the effect of resistance exercise on mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria exist as dynamic networks that are continuously remodeling through fusion and fission. The purpose of this study was to investigate the effect of acute and chronic resistance exercise, which induces muscle hypertrophy, on the expression of proteins related to mitochondrial dynamics in rat skeletal muscle. Resistance exercise consisted of maximum isometric contraction, which was induced by percutaneous electrical stimulation of the gastrocnemius muscle. Our results revealed no change in levels of proteins that regulate mitochondrial fission (Fis1 and Drp1) or fusion (Opa1, Mfn1, and Mfn2) over the 24-h period following acute resistance exercise. Phosphorylation of Drp1 at Ser616 was increased immediately after exercise (P < 0.01). Four weeks of resistance training (3 times/week) increased Mfn1 (P < 0.01), Mfn2 (P < 0.05), and Opa1 (P < 0.01) protein levels without altering mitochondrial oxidative phosphorylation proteins. These observations suggest that resistance exercise has little effect on mitochondrial biogenesis but alters the expression of proteins involved in mitochondrial fusion and fission, which may contribute to mitochondrial quality control and improved mitochondrial function.
    Full-text · Article · Jul 2015 · Applied Physiology Nutrition and Metabolism
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