Abstract
Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca2+ handling.
Highlights
Mitochondrial quality control is essential in highly structured cells such as neurons and muscles
Mitochondrial fission depends on the cytosolic GTPase dynamin-related protein 1 (DRP1), which is recruited to the outer mitochondrial membrane and oligomerizes to form active GTPdependent mitochondrial fission sites[7]
Because DRP1 level decreases in muscle during ageing and in different conditions of muscle wasting[13,14,16,17,18,20], we generated a muscle-specific Drp[1] knockout mouse by crossing the Drp1fl/fl mice with MLC1f-Cre transgenic mice (Drp1−/−), where Cre recombinase is expressed in differentiated muscle cells and not in muscle stem cells or in myocytes[21]
Summary
Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. The maintenance of a functional mitochondrial network is important for tissues that are highly structured and metabolically active, such as neurons, cardiac, and skeletal muscles These tissues are constituted by post-mitotic cells that do not divide. Loss-of-function mutation in the DRP1 receptor, MiD49, causes severe myopathy in humans[20] These observations suggest that changes of mitochondrial shape might be an important player in determining muscle mass maintenance, homeostasis, and metabolism. To understand the physiological relevance of the fission machinery in muscle homeostasis, we generate two mouse models lacking Drp[1] in skeletal muscle and show that these mice develop a lethal mitochondrial myopathy caused by activation of protein breakdown, ER stress, hypoglycemia, and abnormalities in Ca2+ homeostasis
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