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Mitochondria produce most of the chemical energy that powers a cell. Likewise, their dysfunction is associated with a wide variety of illnesses: autism, Alzheimer's, dementia, schizophrenia, Parkinson's, epilepsy, stroke, cancer, chronic fatigue syndrome as well as cardiovascular disease.
These disorders are chameleon-like, changing in form, varying widely from individual to individual. There are a number of different factors that can cause mitochondria (mtDNA) to misbehave, with mutations playing an outsize role. Now, a team of researchers at Vanderbilt University has discovered that mutant mtDNA may cause diseases by behaving "selfishly," in a fashion that benefits only them, while harming their host.
Vanderbilt researchers identified specific molecular responses that mutant mtDNA can use to circumvent cell control. Detailed understanding of how these molecular pathways do or don't work, would help researchers develop effective treatments for mitochondrial disorders.
"About one newborn in every 200 inherits a potentially pathological mitochondrial disease which manifests in about one adult out of 5,000," according to Maulik Patel PhD, Assistant Professor of Biological Sciences, who directed the Vanderbilt research. The work is described in the paper "Homeostatic responses regulate selfish mitochondrial genome dynamics in C. elegans" published in the July 12 issue of the journal Cell Metabolism.
"Once we know the mechanisms that mutant mitochondria use to evade cellular regulation, then we can develop drugs to target these pathways and prevent the mutations from spreading," adds Patel.
Mitochondria are a unique feature in eukaryotic cells — meaning cell types surrounded by a cell wall, found in plants and animals. It is generally accepted that mitochondria were originally independent bacteria that developed an ability to tap highly toxic oxygen molecules for their own powerful energy source. Some prokaryote cells, like our own, found ways to convert mitochondria into"endosymbionts" — meaning they became able to live within the body of another organism.
Self-contained mitochondria are generally known as "the powerhouses of the cell," involved in cell cycle regulation and cell growth.
One of the things that make mitochondria unique is that they retain their own DNA. However, their genome is extremely small with a closed ring of 37 genes inherited solely from the mother — compared to the massive human genome. Additionally, the number of mtDNA copies in human cells differs widely by cell type. For example, human blood cells don't carry any mitochondria, while human liver cells can house thousands of mitochondria apiece.
Normally, all the copies of mtDNA are the same. However, molecular mechanisms in cells disassemble and destroy unneeded or improperly functioning components, including mitochondria, as necessary. So, mitochondria can be replicated and destroyed at a very high rate resulting in mutant mtDNA. If mtDNA mutations reach very high levels, they become pathogenic to the cell or tissue.
Patel and his colleagues studied the nature of mitochondrial disorders as found in the transparent roundworm Caenorhabditis elegans (C. elegans for short). C. elegans is a widely used animal model for exploring basic processes in development and behavior in multi-cellular organisms like ourselves. They found cells activate two specific responses to dysfunctional mitochondria. Paradoxically, these responses inadvertently allow mutant mtDNA to continue to propagate and proliferate.
Cells continuously monitor the health of mitochondria to repair problems. In the procedure called mitochondrial unfolded protein response, unfolding the protein alleviates the dysfunctional mitochondria, while protecting it from being destroyed by a cell's disassembly mechanism.
The research was funded in part by National Institutes of Health grants 5T32GM008554-18 and P30 AI110527.
Some of the diseases linked to mutations in mitochondrial DNA.
Image Credit: Maulik Patel, Vanderbilt University