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CLPX acquires an iron-sulfur cluster to maintain mitochondrial unfolded protein response in cancer cells

ABSTRACT: The proper function of UPRmt requires intact protein synthesis and mitochondrial import machineries. To explain why iron deficiency could inhibit UPRmt activity, we carried out proteomic assays on HepG2 cells to search for differentially-expressed mitochondrial proteins (DEMPs) associated with cytosolic and mitochondrial protein synthesis or mitochondrial import before and after DFX treatment.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: 成全黄

LAB HEAD: Gang Liu

PROVIDER: PXD069791 | Pride | 2026-06-15

REPOSITORIES: Pride

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			Action	DRS
	Con_1.raw	Raw
	Con_2.raw	Raw
	Con_3.raw	Raw
	DFX_1.raw	Raw
	DFX_2.raw	Raw

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Publications

CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.

Huang Chengquan C Zhang Yixue Y Gao Han H Song Yuxin Y Hu Shunchang S Sun Chaoyue C Duan Shiwen S Ma Dongxiao D Jiang Xiumei X Liu Gang G

Nature communications 20260609 1

Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to e ...[more]

PMID: 42265110

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Project description:The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.

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Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation

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