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Nuclear responses to depletion of mitochondrial DNA in human cells
K Li1, P D Neufer, R S Williams
1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas 75235-8573, USA.
Abstract:
The derivation of human cell lines devoid of mitochondrial (mt) DNA (rho 0) provides an opportunity to study nuclear responses to a chronic impairment of mitochondrial oxidative phosphorylation. Expression of several nuclear genes is induced in human rho 0 cells, including those encoding integral proteins of the mitochondrial inner membrane, intermediate filaments, and ribosomes. In contrast to conditions in which mitochondrial respiration is altered acutely, expression of heat shock proteins and immediate early genes is not induced. Mitochondria from rho 0 cells maintain a transmembrane electrochemical potential and are distributed within the cytoplasm of these cells in a manner indistinguishable from that of wild-type cells. We conclude that a chronic deficiency of mitochondrial oxidative phosphorylation produced by elimination of mtDNA is associated with a different pattern of gene induction than that provoked by other acute or subacute conditions that impair mitochondrial respiration or create energy demands in excess of mitochondrial respiratory capacity.
Insights
Human cells lacking mitochondrial DNA (rho 0 cells) show specific nuclear gene induction in response to chronic impaired mitochondrial function. This differs from responses seen in acute mitochondrial stress, highlighting distinct cellular adaptation pathways.
Area of Science:
- Cellular and Molecular Biology
- Mitochondrial Biology
- Genetics
Background:
- Mitochondrial oxidative phosphorylation is crucial for cellular energy production.
- Understanding nuclear responses to mitochondrial dysfunction is key to cellular health.
- Human cell lines lacking mitochondrial DNA (rho 0 cells) offer a model for chronic mitochondrial impairment.
Purpose of the Study:
- To investigate nuclear gene expression patterns in human rho 0 cells with chronic mitochondrial impairment.
- To compare these responses to acute alterations in mitochondrial respiration.
Main Methods:
- Derivation of human cell lines devoid of mitochondrial DNA (rho 0 cells).
- Analysis of nuclear gene expression in rho 0 cells compared to wild-type.
- Assessment of mitochondrial transmembrane potential and distribution in rho 0 cells.
Main Results:
- Specific nuclear genes, including those for mitochondrial inner membrane proteins, intermediate filaments, and ribosomes, were induced in rho 0 cells.
- Unlike acute stress models, heat shock proteins and immediate early genes were not induced.
- Mitochondria in rho 0 cells retained electrochemical potential and normal distribution.
Conclusions:
- Chronic deficiency of mitochondrial oxidative phosphorylation due to mtDNA elimination elicits a distinct gene induction pattern.
- This pattern differs from responses to acute mitochondrial respiration impairment or high energy demand.
- Cellular adaptation to chronic mitochondrial dysfunction involves specific nuclear gene regulation.