LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function

Yujie Li; Dawei Huang; Lianqun Jia; Fugen Shangguan; Shiwei Gong; Linhua Lan; Zhiyin Song; Juan Xu; Chaojun Yan; Tongke Chen; Yin Tan; Yongzhang Liu; Xingxu Huang; Carolyn K Suzuki; Zhongzhou Yang; Guanlin Yang; Bin Lu

doi:10.34133/research.0175

LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function

Research (Wash D C). 2023 Jun 16:6:0175. doi: 10.34133/research.0175. eCollection 2023.

Authors

Yujie Li^{1

2

3}, Dawei Huang², Lianqun Jia⁴, Fugen Shangguan^{2

5}, Shiwei Gong², Linhua Lan^{2

5}, Zhiyin Song⁶, Juan Xu⁷, Chaojun Yan⁶, Tongke Chen⁸, Yin Tan⁹, Yongzhang Liu², Xingxu Huang¹⁰, Carolyn K Suzuki¹¹, Zhongzhou Yang¹², Guanlin Yang⁴, Bin Lu^{1

2

3}

Affiliations

¹ The Affiliated Nanhua Hospital and School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
² School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
³ National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China.
⁴ Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China.
⁵ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁶ Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
⁷ Nanjing Maternity and Child Health Care Hospital, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing 210004, China.
⁸ Animal Center, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
⁹ Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
¹⁰ School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
¹¹ Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School-Rutgers, The State University of New Jersey, Newark, NJ, USA.
¹² State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China.

Abstract

Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis. In particular, the mitochondria-endoplasmic reticulum (ER) membrane contact site (MAM) is known to regulate ion and lipid transfer, as well as signaling and organelle dynamics. However, the regulatory mechanisms of MAM formation and their function are still elusive. Here, we identify mitochondrial Lon protease (LonP1), a highly conserved mitochondrial matrix protease, as a new MAM tethering protein. The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation. Furthermore, deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER (UPR^ER). Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling. These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity, mitochondrial dynamics, and UPR^ER, offering exciting new insights into the potential therapeutic strategy for heart failure.