Mitophagy induction promotes the maturation of hiPS-derived cardiomyocytes

Q: What is the clinical evidence from this study?

Population: Cardiomyocyte differentiation and maturation. Intervention: P62-mediated mitophagy inducer (PMI) vs. Untreated hiPS-CMs and Parkin-/- CMs. Primary outcome: Mitophagy levels, mitochondrial function, and cardiomyocyte maturation markers.

Q: What does this research mean for the field?

Mitophagy activation by P62-mediated mitophagy inducer promotes early differentiation and development of hiPS-CMs and reduces impairment caused by Parkin deletion. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Ying Zhang; Min Zhang; Junming Zhang; Ziwei Wang; Yan Chen; Junhao Han; Kongrui Lu; 贾莉; Yuan Qin; Guohua Gong

doi:10.1186/s12964-026-03212-4

September 14, 2026Cell Communication and SignalingOpen Access

Mitophagy induction promotes the maturation of hiPS-derived cardiomyocytes

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Key result

Mitophagy activation with PMI enhances early differentiation of hiPS-CMs and rescues Parkin-deficient impairment.

Key Points

To investigate the functional role and regulatory mechanisms of Parkin-mediated mitophagy during the early differentiation and maturation of human-induced pluripotent stem cell-derived cardiomyocytes.
Depleted Parkin in human-induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and evaluated pluripotency, cell viability via BrdU and CCK-8 assays, and apoptosis via TUNEL staining.
Differentiated hiPSCs into cardiomyocytes (hiPS-CMs) using a serum-free protocol with optimized CHIR-99,021 concentrations.
Assessed mitochondrial morphology, membrane potential, ROS generation, respiratory flux, and the rescue effects of the p62-mediated mitophagy inducer (PMI).
Parkin knockout impaired mitophagy flux, resulting in TOM20 and p62 accumulation, reduced LC3 expression, decreased lysosome abundance, and increased apoptosis without altering pluripotency markers NANOG, OCT-4, or SOX2.
Parkin deficiency reduced ATP levels, decreased maximal respiratory reserve, lowered mitochondrial membrane potential, and elevated reactive oxygen species (ROS), accompanied by MFN2 downregulation and DRP1 upregulation.
Enhancement of mitophagy using PMI promoted the early differentiation and development of hiPS-CMs and mitigated the maturation and developmental impairments caused by Parkin deletion.

Structured PICO

P

Population

In vitro study utilizing human-induced pluripotent stem cell-derived cardiomyocytes to evaluate the role of mitophagy in early cardiac differentiation and development.

I

Intervention

Parkin deletion via CRISPR/Cas9 and/or P62-mediated mitophagy inducer (PMI) 10 µmol/L

C

Comparator

Control hiPS-CMs

O

Outcome

Cardiomyocyte differentiation and maturation (assessed via mitochondrial homeostasis, ROS levels, respiratory function, and metabolic conversion)surrogate

Mitophagy activation promotes the early differentiation and maturation of human-induced pluripotent stem cell-derived cardiomyocytes, offering insights into mitochondrial quality control in cardiac development.

Implication

May enhance hiPS-CM maturation in models; leaves open translation to clinical cardiac regeneration.

Abstract

Mitophagy dysfunction is an important contributor to the occurrence of cardiovascular diseases. Parkin-mediated mitophagy directs perinatal cardiomyocyte metabolism maturation, but its role during the earlier stage of cardiomyocyte differentiation is not fully elucidated. Human-induced pluripotent stem cell differentiated cardiomyocytes (hiPS-CMs) offer the possibility of investigating mitophagy in the differentiation process of cardiomyocytes in vitro. Therefore, in this study, we investigated the role of mitophagy involved in the differentiation and early development of hiPS-CMs. We found that mitophagy was impaired by Parkin knockdown, resulting in the inhibition of early differentiation and the development of hiPS-CMs. P62-mediated mitophagy inducer (PMI), a mitophagy enhancer, promotes early differentiation and development of hiPS-CMs and reduces the impairment of the differentiation and development of hiPS-CMs mediated by Parkin deletion. Furthermore, during differentiation and development, mitophagy plays an important role in maintaining the balance of mitochondrial homeostasis, reducing ROS accumulation, improving respiratory function, and promoting metabolic conversion. These results suggest that mitophagy activation promotes early differentiation and early development of hiPS-CMs.

Discussion

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Cite This Study

Zhang et al. (2026) studied Cardiomyocyte differentiation and maturation. P62-mediated mitophagy inducer (PMI) vs. Untreated hiPS-CMs and Parkin-/- CMs was evaluated on Mitophagy levels, mitochondrial function, and cardiomyocyte maturation markers. Mitophagy activation with PMI promoted early differentiation and development of hiPS-CMs, and rescued the impairment of differentiation mediated by Parkin deletion.

synapsesocial.com/papers/6aa9016aeed42882c1fc17fd https://doi.org/10.1186/s12964-026-03212-4

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Mitophagy induction promotes the maturation of hiPS-derived cardiomyocytes

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

Mitophagy induction promotes the maturation of hiPS-derived cardiomyocytes

Key Points

Structured PICO

Implication

Abstract

Discussion

Cite This Study

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