Mitochondrial Dysfunction as a Context-Dependent Driver and Amplifier of the SASP: Targeting the mtDNA-cGAS-STING Axis for Next-Generation Senotherapeutics.

Authors

Hamza Kamaran Hama, Mohammed Ali Hama, Musa M Zorab, Amirreza Gholami, Ammar Mohammed Al-Farga

Published in

Journal of cellular and molecular medicine. Volume 30. Issue 21.

Abstract

Cellular senescence combines stable cell-cycle arrest with mitochondrial and innate immune remodelling that shapes the senescence-associated secretory phenotype (SASP). This narrative review evaluates mitochondrial dysfunction as a context-dependent initiator or amplifier of senescence and examines mitochondrial DNA (mtDNA) sensing through cGAS-STING as a driver of SASP regulation. We distinguish mitochondrial damage, cytosolic mtDNA exposure, pathway activation, SASP transcription, secretion, paracrine activity and tissue outcomes as separate levels of evidence. The strongest mechanistic studies link BAX/BAK-mediated minority mitochondrial outer-membrane permeabilization, VDAC1 oligomerization, defective mitophagy or abnormal mtDNA composition to cytosolic mtDNA, cGAS-STING activation and SASP modulation through genetic or pharmacological perturbation. However, pathway architecture varies across cell types, tissues and senescence triggers, and nuclear DNA, micronuclei, retroelements and mitochondrial RNA can activate overlapping inflammatory programmes. Preclinical evidence therefore supports STING inhibition primarily as a senomorphic, anti-inflammatory and tissue-protective strategy rather than a senolytic intervention. Mitophagy enhancement, inhibition of mtDNA release, targeted protein degradation and precision delivery offer complementary approaches, but human efficacy remains unestablished. Clinical translation will require standardized biomarkers, biologically informed patient selection, pharmacodynamic confirmation, tissue-restricted or reversible modulation and prospective assessment of antiviral, antitumour and long-term safety. Overall, the mitochondrial dysfunction-mtDNA-cGAS-STING axis is a mechanistically credible but context-dependent therapeutic framework whose clinical value will depend on validated pathway engagement and appropriately timed clinical intervention.

PMID:
42989704
Bibliographic data and abstract were imported from PubMed on 06 Nov 2026.

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