Lipin-1 regulates Bnip3–mediated mitophagy in glycolytic muscle

Abdullah A. Alshudukhi, Jing Zhu, Dengtong Huang, Abdulrahman Jama, Jeffrey D. Smith, Qing Jun Wang, Karyn A. Esser, Hongmei Ren

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Autophagy of mitochondria (mitophagy) is essential for maintaining muscle mass and healthy skeletal muscle. Patients with heritable phosphatidic acid phosphatase lipin-1–null mutations present with severe rhabdomyolysis and muscle atrophy in glycolytic muscle fibers, which are accompanied with mitochondrial aggregates and reduced mitochondrial cytochrome c oxidase activity. However, the underlying mechanisms leading to muscle atrophy as a result of lipin-1 deficiency are still not clear. In this study, we found that lipin-1 deficiency in mice is associated with a marked accumulation of abnormal mitochondria and autophagic vacuoles in glycolytic muscle fibers. Our studies using lipin-1–deficient myoblasts suggest that lipin-1 participates in B-cell leukemia (BCL)-2 adenovirus E1B 19 kDa protein–interacting protein 3 (Bnip3)–regulated mitophagy by interacting with microtubule-associated protein 1A/1B-light chain (LC)3, which is an important step in the recruitment of mitochondria to nascent autophagosomes. The requirement of lipin-1 for Bnip3–mediated mitophagy was further verified in vivo in lipin-1–deficient green fluorescent protein-LC3 transgenic mice (lipin-12/2-GFP-LC3). Finally, we showed that lipin-1 deficiency in mice resulted in defective mitochondrial adaptation to starvation-induced metabolic stress and impaired contractile muscle force in glycolytic muscle fibers. In summary, our study suggests that deregulated mitophagy arising from lipin-1 deficiency is associated with impaired muscle function and may contribute to muscle rhabdomyolysis in humans.

Original languageEnglish
Pages (from-to)6796-6807
Number of pages12
JournalFASEB Journal
Volume32
Issue number12
DOIs
StatePublished - Dec 2018

Bibliographical note

Publisher Copyright:
© FASEB

Keywords

  • Contractile force
  • Fld
  • LC3
  • Mitochondrial autophagy
  • Rhabdomyolysis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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