Dataset Information

Polyunsaturated fatty acid sequestration protects against ferroptosis in mitochondrial dysfunction

ABSTRACT: While impaired energy production is a hallmark of mitochondrial oxidative phosphorylation (OXPHOS) defects, many OXPHOS aberrations permit residual energy output, leading to pathologies driven by secondary metabolic disturbances, such as redox stress. We have discovered that cells with OXPHOS deficiencies accumulate triacylglycerols enriched in polyunsaturated fatty acids (PUFAs), which are stored in lipid droplets. Sequestration of PUFAs is a critical component of a broader stress response, which also includes downregulation of cellular desaturases and upregulation of glutathione peroxidase 4 (GPX4). Here, we demonstrate that this mechanism represents a physiologically relevant protective strategy, manifesting in the cells under hypoxia and fibroblasts derived from patients with primary mitochondrial complex IV deficiency. As proof of principle, we observed elevated PUFA-enriched triacylglycerols in the plasma of patients with Myoclonic Epilepsy with Ragged Red Fibres (MERRF). Our findings reveal a novel protective mechanism against ferroptosis, which preserves membrane integrity when mitochondrial respiration is compromised.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Marek Vrbacky

LAB HEAD: Alena Pecinova

PROVIDER: PXD069869 | Pride | 2026-07-12

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	PLK057_EXPL_210726_01_4uL_DIA_150M_120G.raw	Raw
	PLK057_EXPL_210726_05_4uL_DIA_150M_120G.raw	Raw
	PLK057_EXPL_210726_06_4uL_DIA_150M_120G.raw	Raw
	PLK057_EXPL_210726_07_4uL_DIA_150M_120G.raw	Raw
	PLK057_EXPL_210726_09_4uL_DIA_150M_120G.raw	Raw

Items per page:

1 - 5 of 49

Similar Datasets

Project description:Background: Transcription control of mitochondrial metabolism is essential for cellular function. A better understanding of this process will aid the elucidation of mitochondrial disorders, in particular of the many genetically unsolved cases of oxidative phosphorylation (OXPHOS) deficiency. Yet, to date only few studies have investigated nuclear gene regulation in the context of OXPHOS deficiency. In this study, we combined RNA sequencing of human complex I-deficient patient cells across 32 conditions of perturbed mitochondrial metabolism, with a comprehensive analysis of gene expression patterns, co-expression calculations and transcription factor binding sites. Results: Our analysis shows that OXPHOS genes have a significantly higher co-expression with each other than with other genes, including mitochondrial genes. We found no evidence for complex-specific mRNA expression regulation in the tested cell types and conditions: subunits of different OXPHOS complexes are similarly (co-)expressed and regulated by a common set of transcription factors. However, we did observe significant differences between the expression of OXPHOS complex subunits compared to assembly factors, suggesting divergent transcription programs. Furthermore, complex I co-expression calculations identified 684 genes with a likely role in OXPHOS biogenesis and function. Analysis of evolutionarily conserved transcription factor binding sites in the promoters of these genes revealed almost all known OXPHOS regulators (including GABP, NRF1/2, SP1, YY1, E-box factors) and a set of six yet uncharacterized candidate transcription factors (ELK1, KLF7, SP4, EHF, ZNF143, and EL2). Conclusions: OXPHOS genes share an expression program distinct from other mitochondrial genes, indicative of targeted regulation of this mitochondrial sub-process. Within the subset of OXPHOS genes we established a difference in expression between subunits and assembly factors. Most transcription regulators of genes that co-express with complex I are well-established factors for OXPHOS biogenesis. For the remaining six factors we here suggest for the first time a link with transcription regulation in OXPHOS deficiency. RNA-SEQ of whole cell RNA in 2 control and 2 complex I deficient patient fibroblast cell lines treated with 4 compounds in duplicate, resulting in a total of 2x2x4x2=32 samples

Dataset Information

Polyunsaturated fatty acid sequestration protects against ferroptosis in mitochondrial dysfunction

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets