Molecular medicine reportsAug 21, 2026

Mitochondria-related cell death linked to brain damage after blood flow returns: Causes and possible treatments

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 22, 2026

Abstract

Cerebral ischemia-reperfusion injury (CIRI) may drive neuronal death through ferroptosis, an iron-dependent process linked to mitochondrial dysfunction.

Mitochondrial dysfunction is associated with increased neuronal susceptibility to ferroptosis during CIRI.
Key mitochondrial abnormalities include bursts of reactive oxygen species, calcium overload, and issues with mitochondrial quality control.
These mitochondrial issues may amplify lipid peroxidation, contributing to neuronal death.
A multidimensional pathological network is implicated in the progression of CIRI.
Future therapeutic strategies may target mitochondrial processes to develop neuroprotective interventions against ferroptosis in CIRI.

Simplified

Ischemic stroke remains a leading cause of mortality and disability worldwide. Although vascular recanalization is essential for salvaging the ischemic penumbra, subsequent reperfusion may initiate a cascade of secondary brain injury, a pathological process referred to as cerebral ischemia‑reperfusion injury (CIRI). Ferroptosis, an iron‑dependent form of programmed cell death characterized by the excessive accumulation of lipid peroxides and membrane damage, has emerged as a critical driver of neuronal death in CIRI. Growing evidence supports mitochondrial dysfunction as not only a downstream outcome of bioenergetic failure, but also a central regulatory node within the ferroptotic cascade. The present review systematically summarizes how mitochondrial dysfunction increases neuronal susceptibility to ferroptosis across the pathophysiological progression of CIRI, with a particular focus on the underlying mechanisms. Specifically, a multidimensional pathological network composed of multiple mitochondrial abnormalities, including mitochondrial reactive oxygen species bursts, Ca2+ overload and disruption of the mitochondrial quality control system, encompassing mitochondrial biogenesis, mitochondrial dynamics and mitophagy, synergistically amplifies lipid peroxidation and drives neuronal ferroptosis. Finally, advances and future perspectives regarding mitochondria‑centered therapeutic strategies are highlighted, offering novel insights into the development of targeted neuroprotective interventions against CIRI‑induced ferroptosis.

Mitochondria-related cell death linked to brain damage after blood flow returns: Causes and possible treatments

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