ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
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2025-05
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Abstract
MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1-MPC2 to maintain the integrity and oligomerization of MPC1-MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.
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Hsu, Che-Chia, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, et al. (2025). ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression. Nature cell biology, 27(5). pp. 847–862. 10.1038/s41556-025-01651-8 Retrieved from https://hdl.handle.net/10161/33823.
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Scholars@Duke
Che-Chia Hsu
My research has focused on mitochondrial functions in cancer metabolism and understand the role of mitochondrial dynamics in cellular function and human diseases including cancers. Additionally, I also continuously dissect cancer metabolism and identifying potential metabolic vulnerabilities of cancer initiation, progression and metastasis using several in vitro, ex vivo and in vivo genetical approaches such as CRISPR/Cas9 knockout, mouse/ human organoid cultures and genetically engineered mouse models, thereby characterizing molecular mechanisms regulated by metabolic pathways and developing potential metabolic interventions for targeting cancers.
Vasudevarao PENUGURTI
My research has focused on cancer cell metabolism and the molecular pathways that regulate posttranslational modifications. In addition, we explore cancer initiation, cell survival, progression, and metastasis using a variety of in vitro, ex vivo, and in vivo genetical approaches, including gene knockdown, CRISPR/Cas9 knockout, molecular biology techniques, biochemical approaches, and genetically engineered mouse and Nude mice models, to characterize molecular mechanisms regulated by metabolic pathways and develop potential metabolic strategies for cancer therapy.
Hui-Kuan Lin
The research interest in Dr. Lin lab is to understand oncogenic networks between oncogenes and tumor suppressor genes, dissect the regulatory mechanisms underlying the crosstalk between ageing and cancer, to unravel the role of posttranslational modifications (PTMs) such as ubiquitination and metabolism in diverse molecular and biological processes important for cancer progression and metastasis, cancer stem regulation, cancer immunity and drug resistance by using biochemical and molecular approaches along with and genetic mouse models, and finally to develop small molecule inhibitors and antibodies targeting critical oncogenic signaling and metabolic vulnerabilities for cancer treatment. His research goals aim to not only reveal fundamental insights and concepts for cancer biology and cancer immunity, but also develop novel paradigms and therapeutic strategies for targeting human cancer and overcoming drug resistance.
Research interests include:
- Crosstalk between oncogenic and tumor suppressor networks
- Posttranslational modifications in signaling and cancer
- Cancer progression and metastasis
- Biology of normal and cancer stem cells
- Metabolism in cancer and ageing
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