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Updated: Jan 9, 2026
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Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
963
Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism
Megha Rajendran1, William M Rosencrans2, Nina A Bautista1
1Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
The Journal of Biological Chemistry
|December 7, 2025
Summary
Voltage-dependent anion channel (VDAC) isoforms have distinct roles in cellular metabolism. VDAC3 KO shifts mitochondria to glutamine dependence, while VDAC1 and VDAC2 KOs impact glycolysis and electron transport chain components, respectively.
Area of Science:
- Mitochondrial biology
- Cellular metabolism
- Molecular cell biology
Background:
- The voltage-dependent anion channel (VDAC) is crucial for mitochondrial outer membrane transport.
- Three mammalian VDAC isoforms (VDAC1, VDAC2, VDAC3) exist with distinct expression patterns.
- While biophysically similar, VDAC isoforms may have unique functional roles due to protein interactions.
Purpose of the Study:
- To investigate the non-redundant functions of VDAC isoforms in cellular metabolism.
- To compare the metabolic and proteomic consequences of individual VDAC isoform knockouts (KOs) in HeLa cells.
Main Methods:
- Generated functional knockouts (KOs) for VDAC1, VDAC2, and VDAC3 in HeLa cells.
- Performed comparative metabolic activity assays.
- Conducted proteomic analysis to identify changes in protein expression.
Main Results:
- VDAC3 KO significantly downregulated electron transport chain (ETC) proteins and induced glutamine dependence in mitochondria.
- VDAC2 KO upregulated ETC components but decreased glutamine metabolic enzymes.
- VDAC1 KO reduced glycolytic activity and mitochondrial hexokinase localization.
Conclusions:
- VDAC isoforms play non-redundant roles in metabolic adaptability, particularly in cancer cells.
- VDAC3 has a critical, uncompensated role in maintaining mitochondrial function.
- Isoform-specific VDAC functions highlight potential therapeutic targets for metabolic reprogramming.
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