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Selfish mitochondria implicated in diseases

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.


According to theory, symbiosis is successful because it provided eukaryotes (cells with walls) an added energy source needed to build multi-cellular organisms like ourselves.


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: "Unlike bacterial infections that tend to be all or nothing, mitochondrial infections can have a lot of individual differences. One person with a mutation load of 50 percent might be symptom free while another person with 80 percent might have severe symptoms."

In addition, mitochondrial diseases are transmitted from mother to child and, except for developmental disorders, tend to develop late in life.


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 have a way to count the number of normal mitochondrial genomes they posess, allowing them to make more mitochondrial genomes when they need more energy.

But, researchers found evidence that some mutant mitochondrial genomes are invisible to the cell's counting machinery.

As a result, cells inadvertently make more copies of the mutant mitochondria in a futile attempt to reach maximum energy needed for that cell.

"Viewed from this perspective, mutant mtDNA can be thought of as selfish entities that exploit a cell's regulatory control mechanisms for their own evolutionary interests."


Maulik Patel PhD, Assistant Professor of Biological Sciences, and director of the Vanderbilt research.


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.

However, researchers found that some mutant mitochondria can self activate the mitochondrial unfolded protein response, causing the cell to tolerate the presence of the mutant and allowing it to proliferate. "These are cases where the mutant mitochondrial genomes exploit cellular defenses for their own 'selfish' interests," explains Patel.

Abstract
Selfish genetic elements have profound biological and evolutionary consequences. Mutant mitochondrial genomes (mtDNA) can be viewed as selfish genetic elements that persist in a state of heteroplasmy despite having potentially deleterious consequences to the organism. We sought to investigate mechanisms that allow selfish mtDNA to achieve and sustain high levels. Here, we establish a large 3.1kb deletion bearing mtDNA variant uaDf5 as a bona fide selfish genome in the nematode Caenorhabditis elegans. Next, using droplet digital PCR to quantify mtDNA copy number, we show that uaDf5 mutant mtDNA replicates in addition to, not at the expense of, wildtype mtDNA. These data suggest existence of homeostatic copy number control for wildtype mtDNA that is exploited by uaDf5 to hitchhike to high frequency. We also observe activation of the mitochondrial unfolded protein response (UPRmt) in animals with uaDf5. Loss of UPRmt results in a decrease in uaDf5 frequency whereas constitutive activation of UPRmt increases uaDf5 levels. These data suggest that UPRmt allows uaDf5 levels to increase. Interestingly, the decreased uaDf5 levels in absence of UPRmt recover in parkin mutants lacking mitophagy, suggesting that UPRmt protects uaDf5 from mitophagy. We propose that cells activate two homeostatic responses, mtDNA copy number control and UPRmt, in uaDf5 heteroplasmic animals. Inadvertently, these homeostatic responses allow uaDf5 levels to be higher than they would be otherwise. In conclusion, our data suggest that homeostatic stress response mechanisms play an important role in regulating selfish mitochondrial genome dynamics.

Team members who contributed to the study were Vanderbilt doctoral students Bryan Gitschlag and Cait Kirby, along with Associate Professor of Molecular Physiology and Biophysics David Samuels, Senior Research Specialists Rama Gangula and Simon Mallal and Major E.B. Shulman, Professor of Infectious Diseases and Inflammation at the Vanderbilt School of Medicine.

The research was funded in part by National Institutes of Health grants 5T32GM008554-18 and P30 AI110527.
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Jul 15, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Some of the diseases linked to mutations in mitochondrial DNA.
Image Credit: Maulik Patel, Vanderbilt University


 


 

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