ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesisand fatty acid oxidation in colorectal cancer
- 1Stanford University
Abstract
Metabolic reprogramming is a hallmark of cancer cells, and stem-like populations often upregulate aldehyde dehydrogenases (ALDHs). Functional studies have established essential roles for individual ALDH isoforms in tumor initiation, progression, and metastasis; however, the mechanisms by which these enzymes promote malignancy remain poorly understood. Here we show that aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme highly expressed in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), generates {gamma}-butyrobetaine (GBB) and {gamma}-aminobutyric acid (GABA) in CRC cells. The biosynthesis of both aminocarboxylic acids has been attributed to the cytosolic enzyme ALDH9A1, and we demonstrate that mitochondrial GBB and GABA are functionally distinct from the cytosolic pools of these metabolites. We further demonstrate that mitochondrial GBB can function as an antiport substrate of carnitine-acylcarnitine translocase (CACT), the transporter that mediates fatty acid uptake into the mitochondrial inner matrix. This activity complements the role of cytosolic GBB as the biosynthetic precursor to carnitine. Accordingly, ALDH1B1 can markedly enhance mitochondrial fatty acid oxidation (FAO), a catabolic process that has been linked to CRC and PDAC stemness, progression, and metastasis. Our findings reveal an unexpected role for ALDH1B1 in carnitine metabolism, GABA biosynthesis, and FAO and illustrate how the compartmental reprogramming of metabolic pathways can promote tumor growth.
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BibTeX
@misc{feng2026aldh1b1,
title = {{ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesisand fatty acid oxidation in colorectal cancer}},
author = {Z. Feng and T. E. Bearrood and S. L. Campbell and A. M. Kinsey and N. Matulionis and C.-H. Chen and T. Seike and L. Leak and A. K. Tarhan and S. J. Dixon and D. Mochly-Rosen and H. R. Christofk and J. K. Chen},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.753323},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.753323v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesisand fatty acid oxidation in colorectal cancer
AU - Z. Feng
AU - T. E. Bearrood
AU - S. L. Campbell
AU - A. M. Kinsey
AU - N. Matulionis
AU - C.-H. Chen
AU - T. Seike
AU - L. Leak
AU - A. K. Tarhan
AU - S. J. Dixon
AU - D. Mochly-Rosen
AU - H. R. Christofk
AU - J. K. Chen
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.753323
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.753323v1
AB - Metabolic reprogramming is a hallmark of cancer cells, and stem-like populations often upregulate aldehyde dehydrogenases (ALDHs). Functional studies have established essential roles for individual ALDH isoforms in tumor initiation, progression, and metastasis; however, the mechanisms by which these enzymes promote malignancy remain poorly understood. Here we show that aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme highly expressed in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), generates {gamma}-butyrobetaine (GBB) and {gamma}-aminobutyric acid (GABA) in CRC cells. The biosynthesis of both aminocarboxylic acids has been attributed to the cytosolic enzyme ALDH9A1, and we demonstrate that mitochondrial GBB and GABA are functionally distinct from the cytosolic pools of these metabolites. We further demonstrate that mitochondrial GBB can function as an antiport substrate of carnitine-acylcarnitine translocase (CACT), the transporter that mediates fatty acid uptake into the mitochondrial inner matrix. This activity complements the role of cytosolic GBB as the biosynthetic precursor to carnitine. Accordingly, ALDH1B1 can markedly enhance mitochondrial fatty acid oxidation (FAO), a catabolic process that has been linked to CRC and PDAC stemness, progression, and metastasis. Our findings reveal an unexpected role for ALDH1B1 in carnitine metabolism, GABA biosynthesis, and FAO and illustrate how the compartmental reprogramming of metabolic pathways can promote tumor growth.
ER -