Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations

By Hsiuchen Chen, Marc Vermulst, Yun E. Wang, A. Chomyn, Thomas A. Prolla, M. Mccaffery, D. C. Chan. Cell, 2010

1,194 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/50807c86a454ab9b4351a34b6db8ee7007dc1524

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Clinical Biochemistry

In Molecular Biology

Citations in the corpus

Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease (2013, positive): “Unopposed ﬁ ssionleads to rapid accumulation of mtDNA mutationsand decreased calcium buffering capacity [144,145].”
Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis (2012, background): “Double ablation of Mfn2 and Mfn1 causes mitochondrial DNA depletion, indicating that these proteins are required for mitochondrial DNA stability (9).”
Mitochondrial dynamics in health and disease: mechanisms and potential targets (2023, background): “260 Fission mediated by Drp1 induces the cytoplasmic stress of mtDNA, which promotes the release of CCL2 by HCC cells via activating the TLR9-mediated NF-B pathway, thereby facilitating M2-polarization and the recruitment of tumor-associated macrophages (TAMs).”
Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation (2011, background): “Several lines of evidence, including the data presented here, indicate that mitochondrial fusion can serve a protective function, leading to the exchange of mitochondrial DNA, reorganization of mitochondrial cristae, and delay in apoptosis (22, 38, 39, 41).”
Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency (2013, background): “Conversely, the reduction in mtDNA copy number has been invoked to explain the mitochondrial dysfunction of fusion- deficient cells from Mfn1, Mfn2-deficient mice (Chen et al., 2010).”
Mitochondrial fusion and fission in cell life and death (2010, background): “A recent study showed that mitochondrial fusion is important for the maintenance of a healthy mitochondrial population in muscle cell”
Metabolic regulation of mitochondrial dynamics (2016, background): “…loss of mitochondrial fusion caused by removal of both mitofusins or Opa1 results in a dramatic decrease in mtDNA content, heterogeneous loss of mtDNA nucleoids and membrane potential, and reduced respiratory chain function in both cultured cells and mouse tissues (Chen et al., 2005, 2010).”
Mitochondria: In Sickness and in Health (2012, background): “In this manner, mitochondrial fusion may buffer partially defects and transient stresses (Chen et al., 2007, 2010; Nunnari et al., 1997).”
Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. (2013, background): “Alterations in nDNA-coded mitochondrial genes could impair energy metabolism by inactivating an OXPHOS polypeptide, perturbing antioxidant defenses, altering mtDNA replication and repair, or affecting mitochondrial quality control through alterations in mitochondrial fission and fusion or in mitopha”