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<p>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 Ca<sup>2+</sup> 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.</p> Graphical abstract <p></p> <p>Schematic diagram illustrating the functional regulation of VDAC2 and its association mechanism with disease occurrence. This schematic highlights the multiple functions of VDAC2 as a core regulatory molecule of the outer mitochondrial membrane, as well as the pathological cascades caused by its dysfunction and potential targeted regulatory strategies. VDAC2: voltage-dependent anion channel 2; MCU: mitochondrial calcium uniporter; MOM: outer mitochondrial membrane; ROS: reactive oxygen species. The figure was created with BioRender.com.</p>

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Research progress on VDAC2 in mitochondrial dysfunction-related diseases

  • 期刊论文

  • 发表日期：

    2026年7月10日

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  • Miao Wang,
  • Yuanyuan Cui,
  • Yili Sun,
  • Jia Li

摘要

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.

Graphical abstract

Schematic diagram illustrating the functional regulation of VDAC2 and its association mechanism with disease occurrence. This schematic highlights the multiple functions of VDAC2 as a core regulatory molecule of the outer mitochondrial membrane, as well as the pathological cascades caused by its dysfunction and potential targeted regulatory strategies. VDAC2: voltage-dependent anion channel 2; MCU: mitochondrial calcium uniporter; MOM: outer mitochondrial membrane; ROS: reactive oxygen species. The figure was created with BioRender.com.