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Mitochondrial Reverse Electron Transport: Mechanisms, Pathophysiological Roles, and Therapeutic Potential
by
, , ,
Yanyu Bao
1,2,3,4, 
Cuilan Hu
1,2,3,4,
Bing Wang
5
,
Xiongxiong Liu
1,2,3,4,
Qingfeng Wu
1,
Dan Xu
1,
Zheng Shi
6 and
Chao Sun
1,2,3,4,* 1
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
2
Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
3
Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
4
University of Chinese Academy of Sciences, Beijing 100049, China
5
Institute for Radiological Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan
6
School of Biopharmaceutical and Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China
*
Author to whom correspondence should be addressed.
Biology 2025, 14(9), 1140; https://doi.org/10.3390/biology14091140
Submission received: 18 July 2025
/
Revised: 27 August 2025
/
Accepted: 27 August 2025
/
Published: 29 August 2025
(This article belongs to the Special Issue Mitochondria and Cardiovascular Diseases)
Simple Summary
Mitochondria normally produce energy through an orderly electron transfer process along the respiratory chain. However, under certain conditions like excess succinate accumulation, electrons can flow backward in a phenomenon called reverse electron transport (RET). This review comprehensively examines RET from multiple perspectives: First, we explain its molecular mechanisms—how high mitochondrial membrane potential and reduced coenzyme Q pool drive electrons to reverse through complex I, generating reactive oxygen species (ROS). Second, we discuss RET’s dual biological roles: while moderate ROS serve as signaling molecules, excessive RET causes oxidative damage. Importantly, we analyze RET’s involvement in diverse physiological processes including immune response regulation, metabolic adaptation, and cell death pathways like ferroptosis and necroptosis. The review then details RET’s pathological impacts across multiple diseases: exacerbating tissue damage in heart attacks and strokes, contributing to neurodegeneration in Alzheimer’s disease, playing complex roles in cancer progression, and influencing host–pathogen interactions in tuberculosis. By systematically integrating current research, we provide a unified framework for understanding RET’s multifaceted nature—from its fundamental biochemical principles to its broad physiological and pathological consequences. This synthesis not only advances basic knowledge of mitochondrial biology but also highlights potential therapeutic strategies targeting RET in various diseases.
Abstract
Mitochondrial reverse electron transport (RET) represents a fundamental but potentially hazardous metabolic process in eukaryotic cells. This review systematically examines current understanding of RET mechanisms and their pathophysiological consequences. RET occurs when electrons flow inversely from reduced coenzyme Q (CoQH2) to complex I, driven by excessive reduction of the CoQ pool and elevated mitochondrial membrane potential, resulting in substantial superoxide production. While moderate RET contributes to physiological redox signaling, sustained RET activation leads to oxidative damage and activates regulated cell death pathways. Notably, RET demonstrates metabolic duality: it facilitates ATP generation through NAD+ reduction while simultaneously inducing mitochondrial dysfunction via reactive oxygen species overproduction. Pathologically, RET has been implicated in myocardial ischemia–reperfusion injury, neurodegenerative disorders including Alzheimer’s diseases, and exhibits context-dependent roles in tumor progression. Emerging evidence also suggests RET involvement in microbial pathogenesis through modulation of host immune responses. These findings position RET as a critical regulatory node in cellular metabolism with broad implications for human diseases. Future investigations should focus on developing tissue-specific RET modulators and elucidating the molecular switches governing its activation threshold, which may yield novel therapeutic strategies for diverse pathological conditions.
