In his Johns Hopkins lab, cell biologist Hiromi Sesaki focuses on the biology of the “mighty mitochondria,” the powerhouse of the cell that turns energy from food into the energy that the cell can use. He’s found that the behavior of the membrane-bound organelle plays an important role in the aging process of our cells — which is vital to his investigations within the CIM-supported Human Aging Project as the 2022 Karen and Ethan Leder CIM Human Aging Project (HAP) Scholar.
Most recently, Sesaki and colleague Miho Iijima, a fellow Johns Hopkins cell biologist, published an influential paper in the journal Nature that showed how a group of proteins linked to Parkinson’s disease and amyotrophic lateral sclerosis (ALS) act as “guardians” of mitochondria. Sesaki says, “These findings should advance our understanding of the development of Parkinson’s disease” — insights that could be key to improving life for the 1 million people in the United States who live with this neurodegenerative condition, which increases in incidence with age. Among the takeaways of the scientists’ study:
Size Matters
Mitochondria must be neither too big nor too small to work well, Sesaki notes, adding that scientists have long known that when mitochondria are stressed too much or are damaged beyond repair, they stop fusing, become smaller and degrade. With damaged mitochondria, cells are not as well-equipped to make energy. In the brain, stressed cells can cause neurodegeneration and neuroinflammation.
Proteins are Key
One way cells respond to mitochondria size-control issues caused by stress or damage is by turning on the activities of several proteins. Two of the proteins, called Parkin and PINK1, hang around the mitochondria’s membrane and work as a pair to enable the mitochondria to fuse or degrade. Abnormalities in the genes for Parkin and PINK1 are associated with the onset of Parkinson’s disease in humans. Another protein linked to ALS, OMA1, is also known to stop mitochondria from fusing upon stress.
A Double Knockout is Damaging
Previous studies have shown in mouse studies that when conditions in cells are normal, removing, or “knocking out,” any one of the genes that encode the Parkin, PINK1 and OMA1 proteins causes no abnormalities in mice or their mitochondria. Sesaki and Iijima wondered: What happens when two of the proteins are knocked out? By knocking out PINK1 and OMA1, the duo found that the double-knockout mice were small and had movement problems, along with excessively fused, oversized mitochondria in their neurons when compared to mice with normal versions of the genes. However, if only one gene is knocked out, the other genes still regulate mitochondrial fusion and mice show no signs of mitochondrial enlargement or dysfunction.
Fusion is “Double-Locked”
Based on their studies of genetically engineered mice with 18 variations of normal and knockout combinations of the three genes, along with others, Sesaki and Iijima now believe that mitochondrial fusion is “double-locked.” That’s because mitochondria have two membranes, so that turning off only one of the genes may disable one membrane but not both, and mitochondria can still fuse and remain somewhat healthy. “Working in tandem, Parkin-PINK1 and OMA1 act as guardians of mitochondria, ensuring that the organelles maintain their normal size and function,” Iijima notes.
Leaks Lead to Inflammation
The scientists also measured mitochondria’s main product — energy in the form of adenosine triphosphate (ATP) — and found no change, suggesting that mitochondrial energy production is not affected. They discovered that when mitochondria got too big, their mitochondrial DNA leaked out into the cytosol, the fluid that fills up the space inside cells. This triggered an increase in the release of interferons, proteins that spark an inflammatory immune response.
“Ultimately, our hope is that by discovering new insights about how Parkinson’s disease develops, we can open the door to therapeutic drug targets.” – Hiromi Sesaki
What’s next: Sesaki and his colleagues plan to advance this work by studying more precisely how mitochondrial DNA leaks out of the organelle when it gets too large. They also want to identify which cell types respond to neuronal mitochondrial DNA release to induce innate immune responses.
“Ultimately,” says Sesaki, “our hope is that by discovering new insights about how Parkinson’s disease develops, we can open the door to therapeutic drug targets.”
