Macrophages induce cardiomyocyte ferroptosis via mitochondrial transfer

  • Free Radic Biol Med. 2022 Sep;190:1-14. doi: 10.1016/j.freeradbiomed.2022.07.015.
Jun Chen  1 ,  Chun-Yan Fu  2 ,  Gerong Shen  2 ,  Jingyu Wang  3 ,  Lintao Xu  3 ,  Heyangzi Li  2 ,  Xi Cao  2 ,  Ming-Zhi Zheng  4 ,  Yue-Liang Shen  2 ,  Jinjie Zhong  5 ,  Ying-Ying Chen  6 ,  Lin-Lin Wang  7
Affiliations
  • 1. Department of Basic Medicine Sciences, And Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 2. Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 3. Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 4. School of Basic Medical Sciences & Forensic Medicine of Hangzhou Medical College, Hangzhou, 310053, China.
  • 5. Department of Basic Medicine Sciences, And Department of Obstetrics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
  • 6. Department of Basic Medicine Sciences, And Department of Obstetrics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China. Electronic address: [email protected].
  • 7. Department of Basic Medicine Sciences, And Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. Electronic address: [email protected].
PMID: 35933052 DOI: 10.1016/j.freeradbiomed.2022.07.015
Abstract

Introduction: Mitochondrial transfer is a new cell-to-cell communication manner. Whether the mitochondrial transfer is also involved in the macrophage infiltration-induced cardiac injury is unclear.

Objectives: This study aimed to determine whether macrophage mitochondria can be transferred to cardiomyocytes, and to investigate its possible role and mechanism.

Methods: Mitochondrial transfer between macrophages and cardiomyocytes was detected using immunofluorescence staining and flow cytometry. Cellular metabolites were analyzed using LC-MS technique. Differentially expressed mRNAs were identified using RNA-seq technique.

Results: (1) After cardiomyocytes were cultured with macrophage-conditioned medium (COND + group), macrophage-derived mitochondria have been found in cardiomyocytes, which could be blocked by dynasore (an inhibitor of clathrin-mediated endocytosis). (2) Compared with control (CM) group, there were 545 altered metabolites found in COND + group, most of which were lipids and lipid-like molecules. The altered metabolites were mainly enriched in the β-oxidation of fatty acids and glutathione metabolism. And there were 4824 differentially expressed mRNAs, which were highly enriched in processes like lipid metabolism-associated pathway. (3) Both RNA-seq and qRT-PCR results found that ferroptosis-related mRNAs such as Ptgs2 and Acsl4 increased, and Gpx4 mRNA decreased in COND + group (P < 0.05 vs CM group). (4) The levels of cellular free Fe2+ and mitochondrial lipid peroxidation were increased; while GSH/GSSG ratio, mitochondrial aspect ratio, mitochondrial membrane potential, and ATP production were decreased in cardiomyocytes of COND + group (P < 0.05 vs CM group). All the above phenomena could be blocked by a Ferroptosis inhibitor ferrostatin-1 (P < 0.05).

Conclusion: Macrophages could transfer mitochondria to cardiomyocytes. Macrophage-derived mitochondria were internalized into cardiomyocytes through clathrin- and/or lipid raft-mediated endocytosis. Uptake of exogenous macrophage mitochondria induced cardiomyocyte injury via triggering Ferroptosis.

Keywords
Cardiomyocytes; Ferroptosis; Macrophages; Mitochondrial transfer.
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