Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial ROS emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle

American Journal of Physiology - Regulatory, Integrative and Comparative Physiology

Acetaldehyde dehydrogenase 2 (ALDH2) is an enzyme involved in redox homeostasis, as well as the detoxification process in alcohol metabolism. Nearly 8% of the world’s population have an inactivating mutation in the ALDH2 gene. However, the expression patterns and specific functions of ALDH2 in skeletal muscles are still unclear. Herein, we report that ALDH2 is expressed in skeletal muscle and is localized to the mitochondrial fraction. Oxidative muscles had a higher ALDH2 protein than glycolytic muscles. We next comprehensively investigated whether ALDH2 knockout in mice induces mitochondrial adaptations in gastrocnemius muscle (for example, content, enzymatic activity, respiratory function, super-complex formation, and functional networking). We found that ALDH2 deficiency resulted in partial mitochondrial dysfunction in gastrocnemius muscle, because it increased mitochondrial ROS emission (DCFH and MitoSOX oxidation rate during respiration) and the frequency of regional mitochondrial depolarization. Moreover, we determined whether ALDH2 deficiency and the related mitochondrial dysfunction trigger mitochondrial stress and quality control responses in gastrocnemius muscle (for example, mitophagy markers, dynamics, and the unfolded protein response). We found that ALDH2 deficiency upregulated the mitochondrial serine protease, Omi/HtrA2 (a marker of activation of a branch of the mitochondrial unfolded protein response). In summary, ALDH2 deficiency leads to greater mitochondrial ROS production, but homeostasis can be maintained via an appropriate stress response.

Yuka Wakabayashi, Yuki Tamura (Corr.), Karina Kouzaki, Naoki Kikuchi, Kenji Hiranuma, Kunitaka Menuki, Takafumi Tajima, Yoshiaki Yamanaka, Akinori Sakai, Keiichi I. Nakayama, Toshihiro Kawamoto, Kyoko Kitagawa, and Koichi Nakazato

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