Loss of Mitochondrial Fusion Enzyme Linked to Age-Related Loss of Muscle Mass

The enzyme mitofusin 2 (Mfn2) was shown to play a key role in the control of age-related muscle mitochondrial damage.

Mitochondrial dysfunction and the accumulation of damaged mitochondria are considered major contributors to the loss of muscle mass (sarcopenia) that comes with aging. However, the molecular mechanisms responsible for these mitochondrial alterations have not been clarified.

When cells experience metabolic or environmental stresses, mitochondrial fusion and fission work to maintain functional mitochondria. An increase in fusion activity leads to mitochondrial elongation, whereas an increase in fission activity results in mitochondrial fragmentation. The components of this process can influence programmed cell death and lead to neurodegenerative disorders such as Parkinson's disease. The shapes of mitochondria are continually changing through the combination of fission, fusion, and motility. Specifically, fusion assists in modifying stress by integrating the contents of slightly damaged mitochondria as a form of complementation. By enabling genetic complementation, fusion of the mitochondria allows for two mitochondrial genomes with different defects within the same organelle to individually encode what the other lacks. In doing so, these mitochondrial genomes generate all of the necessary components for a functional mitochondrion.

Investigators at the Institute for Research in Biomedicine (Barcelona, Spain) reported in the June 22, 2016, online edition of The EMBO Journal that the enzyme mitofusin 2 (Mfn2) played a key role in the control of muscle mitochondrial damage. They demonstrated that aging was characterized by a progressive loss of Mfn2 activity in mouse skeletal muscle and that removal of Mfn2 from skeletal muscle generated a gene signature linked to aging.

Analysis of muscle from mice lacking Mfn2 revealed that aging-induced Mfn2 decrease contributed to age-related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to exacerbated age-related mitochondrial dysfunction.

On the other hand, aging-induced Mfn2 deficiency triggered a ROS (reactive oxygen species)-dependent adaptive signaling pathway that compensated somewhat for the loss of mitochondrial autophagy and minimized mitochondrial damage.

"Sarcopenia is not a minor issue because it impedes some elderly people from going about their everyday lives," said senior author Dr. Antonio Zorzano, head of the Complex Metabolic Diseases and Mitochondria Laboratory at the Institute for Research in Biomedicine. "If we want to boost the health of the elderly then this problem has to be addressed."

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