Article in the latest issue of Annals of Neurology.  

Where do mitochondrial DNA mutations that cause disease and accumulate with age originate from? A new study shows that in human muscle, mtDNA mutations arise near the cell nucleus where they trigger molecular changes that promote their own proliferation, according to an article in the latest issue of Annals of Neurology.




An affected human muscle cell surrounded by normal cells. Mutant mitochondria (red) propagate among healthy mitochondria (green) through the cell cytoplasm.




The article by Vincent et al. identifies the site of origin for mitochondrial DNA mutations – the same kind of mutations that accumulate with aging – and suggests a new mechanism for their proliferation and expansion in human skeletal muscle. This study, a collaboration between Newcastle University and Columbia University, addresses a decades-long conundrum around the intracellular origin of mtDNA mutations and their propagation mechanism in complex human cells.

A new model for the proliferation of mtDNA mutations
Mitochondria are ancient subcellular organelles with their own DNA – the mitochondrial DNA (mtDNA). Within every cell of the body, mitochondria generate the energy and signals required for life. When mitochondria do not work properly, they can cause severe diseases affecting many different organs. In the clinic, some patients also inherit nuclear genetic mutations that promote and accelerate the accumulation of mtDNA mutations, causing severe mitochondrial disorders. It is therefore critical to understand where mtDNA mutations originate and how they propagate.

“We have known for about two decades that mtDNA defects clonally accumulate within brain, muscle, and heart cells, and that they contribute to mitochondrial disease and probably also to aging,” says Professor Sir Doug Turnbull, Director of the Wellcome Centre for Mitochondrial Research at Newcastle University, “but how this process begins has been quite unclear.”

“We combined a number of cellular imaging, biochemical, and molecular genetic methods in muscle samples from patients with genetic mitochondrial disorders”, explains Amy Vincent, the first author on the study. “Our study synergizes with recent studies in worms (Caenorhabditis. elegans) and proposes a mechanism in humans to explain how mtDNA deletions expand inside the cell.” The study also used 3D electron microscopy imaging to demonstrate that the intracellular spread of mtDNA defects follows the natural organization of the mitochondrial network, suggesting that structural factors also influence the spread of mutant mitochondria.

By looking at an old problem with a new set of tools and theory, the study found evidence for a new kind of mitochondrial behavior. A key idea emerging from this work is that mtDNA defects originate as a proliferative perinuclear niche that harnesses internal resources within the cell nucleus to proliferate. “In a way, it is as if mutant mitochondria acquire a cancerous phenotype, hijacking the cell nucleus, and then invading the rest of the cell to the detriment of existing healthy mitochondria”, explains Martin Picard, Columbia University and lead author. “This completely changes how we think about mutant mitochondria, and possibly tells us something about the driving forces that lead to mitochondrial decline in aging and mitochondrial diseases”.

These new principles around the origin and propagation of mutant mitochondria in humans open new questions about mitochondrial signaling in living organisms. These findings may also eventually guide therapeutic approaches that will promote mitochondrial health and prevent the accumulation of mtDNA defects with aging and disease.