BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the “Hole” Story?
- 1Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, and Program in Neuroscience, Baltimore, MD 21201, USA
Abstract
Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.
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BibTeX
@article{zhang2026vdac,
title = {{BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the “Hole” Story?}},
author = {Naibo Zhang and Daniel D. Freeman and Brian M. Polster},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201839},
url = {https://www.mdpi.com/2073-4409/15/20/1839},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the “Hole” Story?
AU - Naibo Zhang
AU - Daniel D. Freeman
AU - Brian M. Polster
PY - 2026
DA - 2026/10/10
JO - Cells
DO - 10.3390/cells15201839
UR - https://www.mdpi.com/2073-4409/15/20/1839
AB - Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.
SN - 2073-4409
ER -