2. Academic Validation
  3. Quantitative proteomic and phosphoproteomic analysis reveal the relationship between mitochondrial dysfunction and cytoskeletal remodeling in hiPSC-CMs deficient in PINK1

Quantitative proteomic and phosphoproteomic analysis reveal the relationship between mitochondrial dysfunction and cytoskeletal remodeling in hiPSC-CMs deficient in PINK1

  • J Transl Med. 2023 Aug 30;21(1):581. doi: 10.1186/s12967-023-04467-y.
Huiwen Liu 1 2,  Li Wang 1 2,  Hao Xu 2 3,  Bin Tan 1 2,  Qin Yi 1 2,  Hongrong Deng 1 2,  Yunxia Chen 1 2,  Bolin He 1 2 4,  Jie Tian 2 5,  Jing Zhu 6 7
Affiliations

Affiliations

  • 1 Ministry of Education Key Laboratory of Child Development and Disorders, Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Blood Transfusion, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Department of Cardiovascular (Internal Medicine), Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 6 Ministry of Education Key Laboratory of Child Development and Disorders, Department of Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 7 Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
PMID: 37649075 DOI: 10.1186/s12967-023-04467-y
Abstract

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are seed cells that can be used for alternative treatment of myocardial damage. However, their immaturity limits their clinical application. Mitochondrial development accompanies cardiomyocyte maturation, and PINK1 plays an important role in the regulation of mitochondrial quality. However, the role and mechanism of PINK1 in cardiomyocyte development remain unclear.

Methods: We used proteomic and phosphoproteomic to identify protein and phosphosite changes in hiPSC-CMs deficient in PINK1. Bioinformatics analysis was performed to identify the potential biological functions and regulatory mechanisms of these differentially expressed proteins and validate potential downstream mechanisms.

Results: Deletion of PINK1 resulted in mitochondrial structural breakdown and dysfunction, accompanied by disordered myofibrils arrangement. hiPSC-CMs deficient in PINK1 exhibited significantly decreased expression of mitochondrial ATP synthesis proteins and inhibition of the oxidative phosphorylation pathway. In contrast, the expression of proteins related to cardiac pathology was increased, and the phosphoproteins involved in Cytoskeleton construction were significantly altered. Mechanistically, PINK1 deletion damaged the mitochondrial cristae of hiPSC-CMs and reduced the efficiency of mitochondrial respiratory chain assembly.

Conclusion: The significantly differentially expressed proteins identified in this study highlight the important role of PINK1 in regulating mitochondrial quality in hiPSC-CMs. PINK1-mediated mitochondrial respiratory chain assembly is the basis for mitochondrial function. Whereas the Cytoskeleton may be adaptively altered in response to mitochondrial dysfunction caused by PINK1 deletion, inadequate energy supply hinders myocardial development. These findings facilitate the exploration of the mechanism of PINK1 in cardiomyocyte development and guide efforts to promote the maturation of hiPSC-CMs.

Keywords

Cytoskeleton; Mitochondrial; PINK1; Phosphoproteomic; Proteomic; Respiratory chain; hiPSC-CMs.

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