1. Academic Validation
  2. Noncanonical TCA cycle fosters canonical TCA cycle and mitochondrial integrity in acute myeloid leukemia

Noncanonical TCA cycle fosters canonical TCA cycle and mitochondrial integrity in acute myeloid leukemia

  • Cancer Sci. 2024 Oct 31. doi: 10.1111/cas.16347.
Atsushi Watanabe 1 2 3 Chartsiam Tipgomut 1 Haruhito Totani 1 Kentaro Yoshimura 4 Tomohiko Iwano 5 Hamed Bashiri 1 Lee Hui Chua 1 Chong Yang 1 6 Toshio Suda 1 6
Affiliations

Affiliations

  • 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 2 Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
  • 3 Department of Pediatrics, Yamanashi Prefectural Central Hospital, Yamanashi, Japan.
  • 4 Department of Anatomy and Cell Biology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
  • 5 Division of Molecular Biology, Center for Medical Education and Sciences, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
  • 6 Institute of Hematology, Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Abstract

Cancer cells rely on mitochondrial Oxidative Phosphorylation (OXPHOS) and the noncanonical tricarboxylic acid (TCA) cycle. In this paper, we shed LIGHT on the vital role played by the noncanonical TCA cycle in a host-side concession to mitochondria, especially in highly energy-demanding malignant tumor cells. Inhibition of ATP-citrate lyase (ACLY), a key Enzyme in the noncanonical TCA cycle, induced Apoptosis by increasing Reactive Oxygen Species levels and DNA damage while reducing mitochondrial membrane potential. The mitochondrial membrane citrate transporter inhibitor, CTPI2, synergistically enhanced these effects. ACLY inhibition reduced cytosolic citrate levels and CTPI2 lowered ACLY activity, suggesting that the noncanonical TCA cycle is sustained by a positive feedback mechanism. These inhibitions impaired ATP production, particularly through OXPHOS. Metabolomic analysis of mitochondrial and cytosolic fractions revealed reduced levels of glutathione pathway-related and TCA cycle-related metabolite, except fumarate, in mitochondria following noncanonical TCA cycle inhibition. Despite the efficient energy supply to the cell by mitochondria, this symbiosis poses challenges related to Reactive Oxygen Species and mitochondrial maintenance. In conclusion, the noncanonical TCA cycle is indispensable for the canonical TCA cycle and mitochondrial integrity, contributing to mitochondrial domestication.

Keywords

ATP‐citrate lyase; antimetabolites; apoptosis; cancer metabolism; cell lines; hematopoietic organ; mitochondria; noncanonical TCA cycle; others; reactive oxygen species.

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