SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12
Yuan Ma,
Suwei Zhu,
Tingting Lv,
Xia Gu,
Hong Feng,
Junhui Zhen,
Wei Xin,
Qiang Wan
Affiliations
Yuan Ma
Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing 100034, China
Suwei Zhu
School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
Tingting Lv
School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
Xia Gu
School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
Hong Feng
Cancer Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250012, China
Junhui Zhen
Department of Pathology, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
Wei Xin
Department of Central Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250012, China; Corresponding author
Qiang Wan
Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Corresponding author
Summary: Mitochondrial DNA (mtDNA) encodes thirteen core components of OXPHOS complexes, and its steady expression is crucial for cellular energy homeostasis. However, the regulation of mtDNA expression machinery, along with its sensing mechanism to energetic stresses, is not fully understood. Here, we identified SQSTM1/p62 as an important regulator of mtDNA expression machinery, which could effectively induce mtDNA expression and the effects were mediated by p38-dependent upregulation of mitochondrial ribosomal protein L12 (MRPL12) in renal tubular epithelial cells (TECs), a highly energy-demanding cell type related to OXPHOS. We further identified a direct binding site within the MRPL12 promoter to ATF2, the downstream effector of p38. Besides, SQSTM1/p62-induced mtDNA expression is involved in both serum deprivation and hypoxia-induced mitochondrial response, which was further highlighted by kidney injury phenotype of TECs-specific SQSTM1/p62 knockout mice. Collectively, these data suggest that SQSTM1/p62 is a key regulator and energetic sensor of mtDNA expression machinery.
