Yourong Ye1,2,3†, Haiyang Li1,2,3†, Fuzhou Liu1,2,3, Yufan Gao1,2,3, Peng Shang1,2,3*, Yangzom Chamba1,2,3*
1College of Animal Science, Xizang Agricultural and Animal Husbandry University, Linzhi, Tibet 860000, China
2The Provincial and Ministerial Co-founded Collaborative Innovation Center for R & D in Tibet Characteristic Agricultural and Animal Husbandry Resources, Linzhi 860000, Xizang, China
3Key Laboratory for the Genetic Improvement and Reproduction Technology of the Xizang Swine, Linzhi 860000, Tibet, China
*Corresponding author’s email: 648510013@qq.com
†These authors contributed equally to this work
Received: 08 July 2025 / Revised: 04 December 2025 / Accepted: 21 December 2025 / Published Online: 15 January 2026
Abstract
Hypoxic environments induce mitochondrial dysfunction, adversely affecting organs and cells. Hypoxia leads to reduced activity of key mitochondrial metabolic enzymes, suppressed protein synthesis, impaired respiratory chain function, abnormal fission and fusion processes, and disrupted calcium homeostasis. These changes result in decreased intracellular ATP production and excessive accumulation of reactive oxygen species (ROS). Hypoxia also diminishes mitochondrial membrane potential, causing leakage of cytochrome C (CytC). This activates the caspase cascade, ultimately inducing apoptosis. This paper systematically elucidates the core pathways of mitochondrial damage and cell death under hypoxia: loss of membrane potential, abnormal opening of the mitochondrial permeability transition pore, release of CytC and apoptosis-inducing factors, and ATP depletion. It also examines impaired respiratory chain activity under hypoxia, alongside reduced oxygen utilization efficiency that exacerbates energy metabolism dysfunction. Under these conditions, cells are forced to activate low-oxygen pathways, further damaging mitochondrial function and establishing a negative feedback loop between hypoxia and mitochondrial dysfunction. Hypoxia also induces alterations in mitochondrial membrane permeability, triggering abnormal exchange of protons and ions across the inner and outer membranes. This facilitates the release of pro-apoptotic factors (such as CytC, Apaf-1, and Smac/DIABLO), activates downstream apoptotic pathways, and exacerbates cellular damage. Additionally, hypoxia enhances the production of ROS in mitochondria, which in turn promote cellular demise by reacting with mitochondrial proteins, lipids, and DNA, consequently compromising mitochondrial structure and function.
Keywords: Cell death, Hypoxia, Mitochondrial dysfunction, Molecular mechanisms
