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New Study Adds An Intriguing Bit to ALS/Mitochondria Puzzle In ALS, trouble is afoot in mitochondria. And while nobody knows why, precisely, new research is showing how seemingly slight disruptions in their normal interactions with the rest of the cell could have great consequences. “Is this the key to understanding the process of ALS?” asks Packard grantee Giovanni Manfredi. “We don’t know.” But given the importance of mitochondria – the organelles that are the body’s major energy source – his research follows a promising avenue for learning about the disease and finding targets for its therapy. It also shines light on how mitochondria interact with other cell systems – a complex and little-studied give-and-take that may be involved in a number of diseases. A report on the work appeared in this month’s online Journal of Biological Chemistry. Manfredi is a neuroscientist with the Weill Medical College of Cornell University. For several years, Manfredi and others have known that ALS’s symptoms begin in both model mice and humans at the same time that mitochondria become misshapen and start to fall apart. Both the animal models and people with the most common familial type of ALS carry a mutated form of the SOD1 (superoxide dismutase) gene that causes their disease. Logically, then, Manfredi’s team has been trying to piece together the SOD1-sick mitochondria connection. It’s part of a major effort by ALS researchers to see, overall, how SOD1 can cause the disease. Normal SOD1, a molecule manufactured in the cell’s cytoplasm, is able to slip through both of the outer and inner membranes that characterize mitochondria. Once inside, it performs a useful service, clearing away toxic charged molecules – free radicals – that build up. Other proteins are “imported” into mitochondria as well, coming in to do various tasks. Not every molecule can enter, however – only those shaped so they’re compatible with mitochondrial systems that pull them in like so many flounder on a fisherman’s deck. In this recent research, Manfredi has focused on an enzyme protein called KARS, one normally given easy entry. Inside mitochondria, KARS plays a quiet but necessary part in the manufacture of specific molecules tailored to their use. What Manfredi discovered was that mutant SOD1, but not healthy (wild type) SOD1 interacts physically with KARS, causing an abnormal structural change that prevents or disrupts KARS’ being imported into mitochondria. “This all happens on the mitochondrial surface,” Manfredi explains. “ KARS, in essence is abducted by mutant SOD1, resulting in its misfolding.” Not only does this prevent KARS from doing its useful role but also, Manfredi speculates, clumps of misfolded KARS and mutant SOD1 may so gum the surface of mitochondria that other necessary proteins are kept from their normal transport in. Further, says Manfredi, warped KARS is likely to be recognized as “bad” by the cell’s housekeeping machinery, placing a strain on that system as well. And neurons, he says, are likely to be more sensitive to these changes than other cells. In the mouse models, for example, non-nervous system tissues looked undamaged. “So we see that a mitochondrial problem can cause ongoing difficulties elsewhere in the cell,” says Manfredi. “Our work adds to the suggestion that there’s a system of protein import in mitochondria whose malfunction could be involved in disease such as ALS*. The idea is an intriguing one.” * Studies elsewhere show that abnormalities in another mitochondrial-entering protein similar to KARS is responsible for the neurodegenerative Charcot-Marie-Tooth disease, a hereditary illness that affects sensation and movement in the lower legs, mostly. |
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