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Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart

Cell Death & Differentiation volume 32, pages 1900–1914 (2025)Cite this article

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Abstract

The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.

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Fig. 1: Reduction of ER-Mito contacts in cardiomyocytes from aging mice leads to accumulation of dysfunctional giant mitochondria.
Fig. 2: Reduction in ER-Mito contacts leads to mitochondrial metabolic dysregulation and autophagic flux blockade in etoposide-treated HL-1 cells.
Fig. 3: Reduction in mitochondrion-associated membranes leading to mitochondrial metabolic dysfunction in aging is associated with decreased mt-PE production.
Fig. 4: PISD deficiency in mitochondria of aged cardiomyocytes inhibits the conversion of PS to PE, impeding mitochondrial PE synthesis.
Fig. 5: Insufficient PE in aged cardiomyocytes impairs autophagosome membrane formation, leading to mitochondrial autophagic flux disruption.
Fig. 6: Targeting LACTB may reverse the PISD-mtPE axis to improve mitochondrial function and metabolism in aged cardiomyocytes.
Fig. 7: Overview of the mechanism by which the aging-associated reduction in ER-mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Change history

  • 14 May 2025

    The affiliations for Guatam Sethi has been updated to affiliation 10.

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Acknowledgements

The Multi-SIM work was supported by Nano Insights (https://www.naxi-tech.com). SIM&ODT analyses were supported by CSR-Biotech (https://www.csr-biotech.com). J.C. acknowledges IP national support, through UID/04923 - Comprehensive Health Research Centre.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82272252, 82270378, and 82372192), Chongqing Talents Program under grant number (cstc2022ycjh-bgzxm0007) and Chongqing Natural Science Foundation General Project (No.CSTB2023NSCQ-MSX0192).

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Author notes

  1. These authors contributed equally: Weilong Hong, Xue Zeng, Ruiyan Ma, Yu Tian.

Authors and Affiliations

  1. Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China

    Weilong Hong, Xue Zeng, Yu Tian, Huimin Miu, Xiaoping Ran, Rui Song, Dapeng Ju, He Huang & Chenyang Duan

  2. Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, P.R. China

    Xue Zeng

  3. Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing, P.R. China

    Ruiyan Ma

  4. Intensive Care Unit, Chongqing Traditional Chinese Medicine Hospital, Chongqing, P.R. China

    Zhenchun Luo

  5. Perioperative and Systems Medicine Laboratory, Department of Anesthesiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, P.R. China

    Daqing Ma

  6. Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK

    Daqing Ma

  7. Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China

    Milad Ashrafizadeh

  8. Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, 769008, Odisha, India

    Sujit Kumar Bhutia

  9. Comprehensive Health Research Centre (CHRC), NOVA Medical School, Faculdade de Ciências Médicas, NMS | FCM, Universidade NOVA de Lisboa, Lisboa, Portugal

    João Conde

  10. Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Gautam Sethi

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Contributions

D.C.Y. and H.W.L. wrote the manuscript. H.W.L. was responsible for most of the cellular experiments. Z.X. and T.Y. were responsible for searching, sorting, and summarizing the references. M.H.M. and J.D.P. were responsible for plasmid construction, R.X.P. assisted with the animal experiments. S.R. assisted with the cellular experiments. D.C.Y., M.R.Y. and L.Z.C. were responsible for the funding of this study. H.H., G.S. and M.D.Q. were responsible for the manuscript editing. M.A, S.K.B and J.C wrote the manuscript and provided the English editing. All authors (regardless of their names) have read, edited, collaborated and approved the final version of the manuscript.

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Correspondence to Gautam Sethi, He Huang or Chenyang Duan.

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All methods were performed in accordance with the relevant guidelines and regulations. All animal experiments were approved by the Institutional Animal Care and Use Committee of the Second Affiliated Hospital of the Chongqing Medical University.

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Hong, W., Zeng, X., Ma, R. et al. Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart. Cell Death Differ 32, 1900–1914 (2025). https://doi.org/10.1038/s41418-025-01511-w

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