Mitochondria as the core regulator of cell death: from classical programmed cell death to the novel mitoxyperiosis pathway
- 1Intensive Care Unit, Wanbei Coal Electric Group General Hospital, Suzhou, Anhui 234000 China
- 2Central Laboratory, Wanbei Coal Electric Group General Hospital, Suzhou, Anhui 234000 China
- 3Department of Radiology, Suzhou Hospital of Anhui Medical University, Suzhou, Anhui 234000 China
Abstract
Mitochondria are recognized as pivotal regulators in cell fate determination, and their dysfunction is implicated in numerous major diseases. While mitochondria control classical programmed cell death pathways, including apoptosis, necroptosis, and pyroptosis, the recent identification of mitoxyperiosis, a BAX/BAK1/BID-dependent and spatially restricted mode of oxidative death, has added complexity to this regulatory framework. Nonetheless, a systematic understanding of how mitochondria coordinate these diverse pathways, particularly the mechanistic relationship between canonical death pathways and this newly identified mode, remains insufficiently explored. In this review, we address three fundamental questions: (1) Through which key molecular mechanisms, including mitochondrial outer membrane permeabilization, reactive oxygen species bursts, mitochondrial DNA release, and alterations in mitochondrial dynamics, do mitochondria regulate each major death pathway? (2) How does mitoxyperiosis diverge from and intersect with classical ferroptosis and other death modalities, and what unique features characterize its execution? (3) What therapeutic opportunities and challenges emerge from targeting mitochondrial death checkpoints to protect cells in pathological conditions and to treat cancer? By critically integrating current evidence, we propose a comprehensive framework that elucidates the regulatory logic of mitochondria-mediated cell death and underscores mitochondrial plasticity as a crucial determinant of cellular outcomes. This perspective not only clarifies the integrative role of mitochondria within the cell death network but also suggests new avenues for developing precision therapies for diseases associated with mitochondrial dysfunction.
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BibTeX
@article{xiao2026mitochondria,
title = {{Mitochondria as the core regulator of cell death: from classical programmed cell death to the novel mitoxyperiosis pathway}},
author = {Jianxiong Xiao and Shuaiyong Qi and Yuzhen Li and Yafen Li and Heng Tang},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08823-6},
url = {https://doi.org/10.1186/s12967-026-08823-6},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Mitochondria as the core regulator of cell death: from classical programmed cell death to the novel mitoxyperiosis pathway
AU - Jianxiong Xiao
AU - Shuaiyong Qi
AU - Yuzhen Li
AU - Yafen Li
AU - Heng Tang
PY - 2026
DA - 2026/08/13
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08823-6
UR - https://doi.org/10.1186/s12967-026-08823-6
AB - Mitochondria are recognized as pivotal regulators in cell fate determination, and their dysfunction is implicated in numerous major diseases. While mitochondria control classical programmed cell death pathways, including apoptosis, necroptosis, and pyroptosis, the recent identification of mitoxyperiosis, a BAX/BAK1/BID-dependent and spatially restricted mode of oxidative death, has added complexity to this regulatory framework. Nonetheless, a systematic understanding of how mitochondria coordinate these diverse pathways, particularly the mechanistic relationship between canonical death pathways and this newly identified mode, remains insufficiently explored. In this review, we address three fundamental questions: (1) Through which key molecular mechanisms, including mitochondrial outer membrane permeabilization, reactive oxygen species bursts, mitochondrial DNA release, and alterations in mitochondrial dynamics, do mitochondria regulate each major death pathway? (2) How does mitoxyperiosis diverge from and intersect with classical ferroptosis and other death modalities, and what unique features characterize its execution? (3) What therapeutic opportunities and challenges emerge from targeting mitochondrial death checkpoints to protect cells in pathological conditions and to treat cancer? By critically integrating current evidence, we propose a comprehensive framework that elucidates the regulatory logic of mitochondria-mediated cell death and underscores mitochondrial plasticity as a crucial determinant of cellular outcomes. This perspective not only clarifies the integrative role of mitochondria within the cell death network but also suggests new avenues for developing precision therapies for diseases associated with mitochondrial dysfunction.
SN - 1479-5876
ER -