Mosaic dysfunction of mitophagy in mitochondrial muscle disease

Mito, Takayuki; Vincent, Amy E.; Faitg, Julie; Taylor, Robert W.; Khan, Nahid Akhtar; McWilliams, Thomas G.; Suomalainen, Anu

doi:10.1016/j.cmet.2021.12.017

Cited by 41 publications

(36 citation statements)

References 52 publications

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“…Hyperactivation of mTORC1, which is known to trigger myopathy 48,49 , is emerging as a common feature in all kinds of muscles disorders, including sarcopenia 50 , myofibrillar myopathy 29 , laminopathies 51 , dystroglycanopathies 52 , and DM1 32 . Interestingly, rapamycin treatment was also shown to confer protection in the setting of mitochondrial myopathies 53 . Our results, therefore, strengthen available literature positioning partial inhibition of mTORC1 as a potential strategy to improve patient outcomes in various muscular diseases 32,50-52,54 .…”

Section: Discussionmentioning

confidence: 99%

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

et al. 2023

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Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.

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Section: Discussionmentioning

confidence: 99%

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

et al. 2023

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“…The physiological functions of lysosomes and mitochondria are compromised in lysosomal storage disease, Parkinson's disease, and mucolipidosis II and III [116]. Mitochondrial myopathies saturate lysosomal capacity, leading to lysosomal dysfunction and autophagosome accumulation [117,118]. Destruction of the mitochondrial lysosomal axis and abnormal extracellular vesicles secretion lead to the aging process and many diseases [119].…”

Section: Crosstalk Between Mitochondria and Other Organellesmentioning

confidence: 99%

Synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles

Zhang

et al. 2023

Cell Death Discov.

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Organelles are functional areas where eukaryotic cells perform processes necessary for life. Each organelle performs specific functions; however, highly coordinated crosstalk occurs between them. Disorder of organelle networks often occur in various diseases. The endoplasmic reticulum (ER) and mitochondria are crucial organelles in eukaryotic cells as they are the material synthesis and oxidative metabolism centers, respectively. Homeostasis and orchestrated interactions are essential for maintaining the normal activities of cells. However, the mode and mechanism of organelle crosstalk is still a research challenge. Furthermore, the intricate association between organelle dyshomeostasis and the progression of many human diseases remains unclear. This paper systematically summarized the latest research advances in the synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles based on recent literature. It also highlights the application potential of organelle homeostasis maintenance as a preventative and treatment strategy for diseases.

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“…These elongated mitochondria appear darker with unclear lumen, suggesting damaged mitochondria as observed during defect in mitophagy. Mitophagy is a quality control mechanism that ensures the elimination of damaged mitochondria 25 and ER contact sites with mitochondria form an exchange space called mitochondria-associated ER membranes (MAMs). The ER is responsible for the formation of mitophagosomes, where damaged mitochondria are ubiquitinated and dynamically encased 26 .…”

Section: Ryr1 Protein Depletion Induces Defects In Er-mitochondria Co...mentioning

confidence: 99%

RyR1 protein content is reduced in inflammatory and mitochondrial myopathies and induces ER stress

Vidal

Fernandez

Wohlwend

et al. 2023

Preprint

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Decreased ryanodine receptor type 1 (RyR1) protein is a hallmark of recessive RYR1-related myopathies (RyR1-RM), which are caused by recessive mutations in the RYR1 gene. It is not clear how the decrease in the RyR1 protein triggers muscular disorders. Furthermore, it is a hot topic whether a decrease in RyR1 protein levels can also occur during non-RYR1-related myopathies. In this study, we first show that reduced RYR1 transcripts are associated with various human myopathies, and that RyR1 protein levels are significantly decreased in muscle samples analysed in inflammatory myopathies (IM) and mitochondrial myopathies (MM), both of which are non-RYR1-RM. Secondly, proteomic data show that exclusive depletion of RyR1 protein in vitro recapitulates the common altered molecular pathways observed during myopathies. RyR1 protein depletion impairs ER-mitochondria tethering and Ca2+ transfer to mitochondria, decreases mitophagy genes and induces an accumulation of dysfunctional mitochondria. This phenomenon is also associated with altered lipid homeostasis with an increase in deleterious sphingolipid species. Finally, decreased RyR1 protein levels lead to an increase in the ER stress markers GRP78-Bip and CHOP in muscle cell in vitro, and in mouse and human muscles. Overall, our results indicate an important role of RyR1 protein depletion and ER stress in the pathogenesis of myopathies.

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Mosaic dysfunction of mitophagy in mitochondrial muscle disease

Cited by 41 publications

References 52 publications

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

Synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles

RyR1 protein content is reduced in inflammatory and mitochondrial myopathies and induces ER stress

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