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How Mitochondrial Dysfunction Leads to Premature Aging

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Researchers at the University at Buffalo and their collaborators have developed powerful new ways to study and potentially reverse the cellular mechanisms that cause mitochondrial diseases and premature aging.


Mitochondria provide the lion’s share of energy that cells need to function normally, so genetic defects in mitochondria can cause severe diseases that can be devastating if not caught and treated early.


But exactly how those mitochondrial defects lead to disease and aging has not been well understood. A paper published in Aging Cell reveals for the first time the connection between mitochondrial defects and key signals in the aging process. In a separate Nature Communications paper, the researchers describe how a new technique they developed based on optogenetics can help restore normal function to abnormal mitochondrial interactions.


Mitochondria and telomeres


The Aging Cell paper links, for the first time, mitochondrial dysfunction to the shortening of telomeres, a key biomarker of premature aging.


“Telomeres are specialized DNA sequences that act as caps that stabilize the ends of chromosomes,” explained Taosheng Huang, MD, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics in the Jacobs School of Medicine and Biomedical Sciences at UB.


“The shortening of telomeres is generally regarded as an important biomarker of aging, but for a long time, no one knew the mechanism. Now we are able to link mitochondrial dysfunction directly to the shortening of telomeres,” said Huang, the paper’s senior author.


The experiments were done with a type of mouse model called the Polg “mutator” in which the mice carry a specific genetic defect that accelerates the rate of mitochondrial DNA mutations.

“We also were able to show in humans how a single nucleotide change in mitochondrial DNA that’s specifically associated with poor function of mitochondria and causing pediatric mitochondrial disorders can accelerate aging,” said Huang. “We found that reactive oxygen species due to poor function of mitochondria leads to increased DNA damage over time.”

The paper is the first to show that the mitochondrial DNA mutations in this model produce more rapid aging as demonstrated by the DNA clock, which estimates an individual’s biological age according to particular chemical markers in the DNA.

Huang noted the research is the result of successful collaboration among all the authors, including Steve Horvath, PhD, professor of human genetics and biostatistics at UCLA, who developed the DNA clock, as well as Patricia Opresko, PhD, associate professor at the University of Pittsburgh, and Sabine Mai, PhD, of the University of Manitoba, both experts in telomeres and telomere damage.

Jesse Slone, PhD, a former postdoc in Huang’s lab at Cincinnati Children’s Hospital Medical Center and now a research assistant professor in the Department of Pediatrics at UB, is co-first author. Additional co-authors are from from Nanchang University and Cincinnati Children’s Hospital Medical Center.

The research was funded by the National Institute of Environmental and Occupational Health and the National Institute on Aging, both of the National Institutes of Health. 


Orchestrating cellular interactions


Published July 25, the Nature Communications paper reveals how optogenetics, which uses light to manipulate cellular activity, can be employed as a tool not only to study, but also to orchestrate cellular organelle interactions in real time. 


The paper focuses on mitochondrial dynamics, the processes that these organelles are constantly undergoing to maintain a healthy balance in the cell. They engage in fission, where one mitochondria divides into two, and fusion, where two fuse together to become one. An imbalance in a cell between the two types of processes can lead to mitochondrial disease. 


“In the Nature Communications paper, we describe a technology that we developed that allows us for the first time to directly manipulate the interactions between mitochondria and other organelles in the cell,” said Huang. 


“By utilizing optogenetics to force a physical interaction between mitochondria and another cellular component, the lysosome, we were able to restore the mitochondria to a more normal size while also improving their energy production functions,” explained Huang. “We believe that this new finding could be used as the basis for future diagnosis and treatments for this group of diseases.” 


The work was made possible by the use of a powerful imaging technology called structural illumination microscopy (SIM) available at the University of Cincinnati, where Huang began this research before taking his current position at UB. SIM allows for extremely high resolution real-time imaging in living cells. 


References:

Yu T, Slone J, Liu W, et al. Premature aging is associated with higher levels of 8‐oxoguanine and increased DNA damage in the Polg mutator mouse. Aging Cell. 2022. doi: 10.1111/acel.13669

Qiu K, Zou W, Fang H, et al. Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts. Nat Commun. 2022;13(1):4303. doi: 10.1038/s41467-022-31970-5


This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.


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