DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass

Giulia Favaro, Vanina Romanello, Tatiana Varanita, Maria Andrea Desbats, Valeria Morbidoni, Caterina Tezze, Mattia Albiero, Marta Canato, Gaia Gherardi, Diego Stefani, Cristina Mammucari, Bert Blaauw, Simona Boncompagni, Feliciano Protasi, Carlo Reggiani, Luca Scorrano, Leonardo Salviati () and Marco Sandri ()
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Giulia Favaro: Venetian Institute of Molecular Medicine
Vanina Romanello: Venetian Institute of Molecular Medicine
Tatiana Varanita: University of Padova
Maria Andrea Desbats: University of Padova
Valeria Morbidoni: University of Padova
Caterina Tezze: Venetian Institute of Molecular Medicine
Mattia Albiero: Venetian Institute of Molecular Medicine
Marta Canato: University of Padova
Gaia Gherardi: University of Padova
Diego Stefani: University of Padova
Cristina Mammucari: University of Padova
Bert Blaauw: Venetian Institute of Molecular Medicine
Simona Boncompagni: via Luigi Polacchi, University G. d’ Annunzio
Feliciano Protasi: via Luigi Polacchi, University G. d’ Annunzio
Carlo Reggiani: University of Padova
Luca Scorrano: Venetian Institute of Molecular Medicine
Leonardo Salviati: University of Padova
Marco Sandri: Venetian Institute of Molecular Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10226-9

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