Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice

作者：Palak Ahuja, Chun Fai Ng, Brian Pak Shing Pang, Wing Suen Chan, Margaret Chui Ling Tse, Xinyi Bi, Hiu-Lam Rachel Kwan, Daniel E. Brobst, Oana Herlea‐Pana, Xiuying Yang, Guanhua Du, Suchaorn Saengnipanthkul, Hye Lim Noh, Baowei Jiao, Jason K. Kim, Chi Wai Lee, Keqiang Ye, Chi Bun Chan · 发表于：Autophagy · 年份：2021 · DOI：10.1080/15548627.2021.1985257 · 被引用次数：115 · 研究领域：Adipose Tissue and Metabolism、Autophagy in Disease and Therapy、Sirtuins and Resveratrol in Medicine

Mitochondrial remodeling is dysregulated in metabolic diseases but the underlying mechanism is not fully understood. We report here that BDNF (brain derived neurotrophic factor) provokes mitochondrial fission and clearance in skeletal muscle via the PRKAA/AMPK-PINK1-PRKN/Parkin and PRKAA-DNM1L/DRP1-MFF pathways. Depleting Bdnf expression in myotubes reduced fatty acid-induced mitofission and mitophagy, which was associated with mitochondrial elongation and impaired lipid handling. Muscle-specific bdnf knockout (MBKO) mice displayed defective mitofission and mitophagy, and accumulation of dysfunctional mitochondria in the muscle when they were fed with a high-fat diet (HFD). These animals also have exacerbated body weight gain, increased intramyocellular lipid deposition, reduced energy expenditure, poor metabolic flexibility, and more insulin resistance. In contrast, consuming a BDNF mimetic (7,8-dihydroxyflavone) increased mitochondrial content, and enhanced mitofission and mitophagy in the skeletal muscles. Hence, BDNF is an essential myokine to maintain mitochondrial quality and function, and its repression in obesity might contribute to impaired metabolism.Abbreviations: 7,8-DHF: 7,8-dihydroxyflavone; ACACA/ACC: acetyl Coenzyme A carboxylase alpha; ACAD: acyl-Coenzyme A dehydrogenase family; ACADVL: acyl-Coenzyme A dehydrogenase, very long chain; ACOT: acyl-CoA thioesterase; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; BDNF: brain derived neurotroph...