Authors
Miao Wang, Yuanyuan Cui, Yili Sun, Jia Li
Published in
Molecular biology reports. Volume 53. Issue 1. Jul 10, 2026. Epub Jul 10, 2026.
Abstract
Mitochondrial dysfunction contributes to numerous human diseases. Voltage‑dependent anion channel 2 (VDAC2) is an essential outer mitochondrial membrane porin with distinct structural and functional properties that are non-redundant with those of VDAC1 and VDAC3. VDAC2 precisely controls ATP, ADP, NADPH and Ca2+ transport, thereby acting as a key hub for energy metabolism, calcium homeostasis, redox balance and cell fate. It directly binds BAX/BAK to differentially regulate apoptosis and is also involved in ferroptosis, necroptosis, Parkin‑dependent mitophagy, and lipid transport through protein interactions and post‑translational modifications. Aberrant expression or dysfunction of VDAC2 promotes tumorigenesis, neurodegenerative diseases, and cardiovascular disorders through metabolic reprogramming, apoptotic imbalance, immune evasion, and impaired mitochondrial quality control. Several small‑molecule compounds and peptides targeting VDAC2 have been developed, providing valuable tools for mechanistic studies and potential therapies for mitochondrial dysfunction‑related diseases. Several major challenges remain, including poor isoform selectivity, a lack of tissue‑specific conditional knockout models, and unclear cross‑species conservation. This review systematically summarizes the structure of VDAC2, its versatile roles in mitochondrial function, disease mechanisms, and advances in pharmacological targeting. We also highlight current limitations and future directions, with the aim of providing a theoretical basis for VDAC2‑targeted drug development and clinical translation.
PMID:
42429877
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.
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