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

Apr 21, 2025

Experts: Weilong Hong,Xue Zeng,Ruiyan Ma,Yu Tian,Huimin Miu,Xiaoping Ran,Rui Song,Zhenchun Luo,Dapeng Ju,Daqing Ma,Milad Ashrafizadeh,Sujit Kumar Bhutia,João Conde,Gautam Sethi,He Huang,Chenyang Duan

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.
© 2025. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

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ABOUT THE EXPERTS

Weilong Hong,Xue Zeng,Ruiyan Ma,Yu Tian,Huimin Miu,Xiaoping Ran,Rui Song,Zhenchun Luo,Dapeng Ju,Daqing Ma,Milad Ashrafizadeh,Sujit Kumar Bhutia,João Conde,Gautam Sethi,He Huang,Chenyang Duan

Weilong Hong

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

Xue Zeng

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

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

Ruiyan Ma

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

Yu Tian

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

Huimin Miu

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

Xiaoping Ran

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

Rui Song

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

Zhenchun Luo

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

Dapeng Ju

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

Daqing Ma

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.

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

Milad Ashrafizadeh

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.

Sujit Kumar Bhutia

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

João Conde

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

Gautam Sethi

Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China. phcgs@nus.edu.sg.

Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. phcgs@nus.edu.sg.

He Huang

Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China. huanghe@cqmu.edu.cn.

Chenyang Duan

Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China. duanchenyang1991@cqmu.edu.cn.