期刊
EMBO JOURNAL
卷 35, 期 15, 页码 1677-1693出版社
WILEY
DOI: 10.15252/embj.201593084
关键词
aging; autophagy; mitochondria; mitophagy; sarcopenia
资金
- FPI fellowship from Ministerio de Educacion y Cultura, Spain
- MINECO [SAF2013-40987R]
- Generalitat de Catalunya [2014SGR48]
- CIBERDEM (Instituto de Salud Carlos III)
- INTERREG IV-B-SUDOE-FEDER (DIOMED) [SOE1/P1/E178]
- ISCIII [PI13/02512]
- FEDER
- Maria de Maeztu Programme for Units of Excellence in RD [MDM-2014-0370]
- AFM
- Fundacio Marato TV3
- CIBERNED
- ICREA Academia (Generalitat de Catalunya)
- Severo Ochoa Award of Excellence from MINECO (Government of Spain)
Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage. We show that aging is characterized by a progressive reduction in Mfn2 in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, analysis of muscle Mfn2-deficient mice revealed that aging-induced Mfn2 decrease underlies the age-related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to an exacerbated age-related mitochondrial dysfunction. Interestingly, aging-induced Mfn2 deficiency triggers a ROS-dependent adaptive signaling pathway through induction of HIF1 alpha transcription factor and BNIP3. This pathway compensates for the loss of mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that Mfn2 repression in muscle during aging is a determinant for the inhibition of mitophagy and accumulation of damaged mitochondria and triggers the induction of a mitochondrial quality control pathway.
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