Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts
Jon Sin,Allen M. Andres,David J. R. Taylor,Thomas A. Weston,Yoshimi Hiraumi,Aleksandr Stotland,Brandon J. Kim,Chengqun Huang,Kelly S. Doran,Roberta A. Gottlieb +9 more
TLDR
Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts, which highlights the integral role of autophagy and mitophagy in myogenic differentiation.Abstract:
Myogenesis is a crucial process governing skeletal muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNM1L/DRP1 (dynamin 1-like)-mediated fragmentation and subsequent removal of mitochondria via SQSTM1 (sequestosome 1)-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha)-mediated biogenesis. Mitochondrial fusion protein OPA1 (optic atrophy 1 [autosomal dominant]) is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that suppressing autophagy with various inhibitors during differentiation interferes with myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation.read more
Citations
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Autophagy: The spotlight for cellular stress responses.
TL;DR: The machinery of Autophagy, the molecular web that connects autophagy to various stress responses like inflammation, hypoxia, ER stress, and various other pathologic conditions is discussed.
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Molecular mechanisms and physiological functions of mitophagy.
TL;DR: In this article, the authors review the current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophathy pathways coordinately modulate mitochondrial fitness and populations.
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Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy.
TL;DR: It is demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury and confirmed that CK2α serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injuries.
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Autophagy, cancer stem cells and drug resistance.
Alexandra G Smith,Kay F. Macleod +1 more
TL;DR: The clinical relevance of this work and how an increased understanding of functions of autophagy in stemness, dormancy and drug resistance could be manipulated for increased therapeutic benefit, including eliminating minimal residual disease and preventing metastasis are discussed.
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BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation
Mark A Lampert,Amabel M. Orogo,Rita H. Najor,Babette C. Hammerling,Leonardo J. Leon,Bingyan J. Wang,Taeyong Kim,Mark A. Sussman,Åsa B. Gustafsson +8 more
TL;DR: The importance of BNIP3L- and FUNDC1-mediated mitophagy as a critical regulator of mitochondrial network formation during differentiation, as well as the consequences of accumulating mtDNA mutations, is demonstrated.
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