Calcium: Not only does it keep our bones strong, it also gives our muscles the strength to move and lift and keeps our neurons firing efficiently so that our thoughts and memory stay sharp – and it does all of this through the help of mitochondria.
Best known for their role in cellular energy production, mitochondria also help manage the cell’s calcium. Researchers have now discovered a link between certain neurological and muscular disorders and mitochondria that can’t control calcium normally, according to results published Nature Genetics in December.
“This study provides a new explanation for why mitochondria stop working in some patients,” says Thomas Jefferson University mitochondrial researcher Gyorgy Hajnoczky, MD, PhD.
Mitochondrial diseases are still poorly understood. They encompass a loose family of conditions that start from a defect in the mitochondria – the power plants of cells.
These diseases lack a diagnostic test and a cure. Researchers continue to work out the genes and mechanisms behind the illnesses, which have an array of symptoms, including seizures, blindness, muscle fatigue and dementia, according to the United Mitochondrial Disease Foundation and the Foundation for Mitochondrial Medicine, and often strike very young patients.
“This is the first time a defect specific to mitochondrial calcium handling has been directly linked to a debilitating human condition,” says Dr. Hajnoczky, director of Jefferson’s recently launched MitoCare Center. “The new findings bring us one step closer to diagnose and treat some mitochondrial diseases.”
The study looked at 15 patients worldwide whose shared set of symptoms suggested they had mitochondrial disease. The researchers, led by Francesco Muntoni at the Medical Research Council Centre for Neuromuscular Diseases in London and Eamonn Sheridan of St. James’s University Hospital, in Leeds, U.K., searched the genomes of these patients and found that each lacked a protein used by the mitochondria to manage calcium. Without the protein, called MICU1, the patients’ cells were incapable of properly regulating the calcium levels in the cell.
“Amazingly, mitochondrial calcium handling has been known for 50+ years but MICU1 was only discovered three years ago,” says Dr. Hajnoczky. Without knowing the specific gene, it would have been impossible to establish a connection with the disease.
Dr. Hajnoczky, who was not involved in the research says he was impressed by the study’s data – “it’s unusual to see 15 patients from many families and different ethnic origins with the same genetic mutation,” he says – but he wasn’t surprised.
Together with his collaborators, including Jefferson colleagues Gyorgy Csordas, MD, and Erin Seifert, PhD, and Vamsi Mootha, MD, from Harvard University, Dr. Hajnoczky had been studying the MICU1 protein from the time it was discovered three years ago. Their group was the first to show that MICU1 acts as a calcium sensor in the mitochondria of mice.
“And now this mechanism has been linked to a severe human disease” says Dr. Hajnoczky.
The work is notable also because it revealed a new combination of symptoms that could help identify other patients with this particular type of mitochondrial disorder. The patients showed involuntary movements, drooping eyelids, muscle weakness and learning difficulties, to name a few, but lacked the deafness and diabetes mellitus that are common to some other mitochondrial diseases.
Linking these symptoms to the gene mutation in MICU1 will help clinicians diagnose mitochondrial disease using genetic screening services currently offered at Jefferson, and could lead to new therapies.
In the future, Dr. Hajnoczky and his colleagues at the MitoCare Center plan to develop models the same mutations as those seen in the patients to try reproduce the disease symptoms. His group hopes to be one of the first to screen for drugs that could help treat patients with a MICU1 mutation.
Ultimately, “by illuminating new mechanisms, this study will energize research, diagnostic and treatment efforts surrounding mitochondrial diseases—it gives us something to build on” says Dr. Hajnoczky.