Mitochondria, the organelle that powers most cells in the body, may be the canary in the coal mine for neurological disease, according to new findings published in the Journal of Cell Biology.
Mitochondrial stress and dysfunction have long been suspected as an early step in diseases like Parkinson’s or Alzheimer’s disease, but Northwestern scientists have uncovered a mechanism that may explain how.
The study found that mitochondrial stress in neurons can cause an enzyme imbalance that contributes to neuronal dysfunction and death. Reversing this imbalance showed promise in cell models, sketching an outline of a future therapy, according to Navdeep Chandel, PhD, the David W. Cugell, MD, Professor and a co-corresponding author of the study.
“In a fly model, we show that mitochondrial dysfunction causes accumulation of L-2-hydroxyglutarate that triggers neurodegeneration resulting in the inability of flies to climb,” said Chandel, a professor of Medicine in the Division of Pulmonary and Critical Care, of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “If this is true in mammals, then it will be a significant finding.”
Mitochondria have three main roles in the cell: generate adenosine triphosphate (ATP), which cells use for energy; regenerate nicotinamide adenine dinucleotide (NAD), which is used for enzyme reactions; and produce reactive oxygen species (ROS), a natural byproduct of the first two processes.
Mitochondrial dysfunction is seen in a variety of neurodegenerative diseases, and conventional thinking sourced this dysfunction to a decrease in ATP production or an increase in ROS, Chandel explained. However, recent studies from the Chandel lab – published in Nature and Nature Cell Biology — suggested that mitochondrial dysfunction is also linked with decreases in NAD. This decrease is coupled with a concurrent increase in L-2-hydroxyglutarate (L-2HG), an enzyme used in a many biological processes.
“Interestingly, humans with mutations in L-2HGDH display progressive postnatal accumulation of L-2HG resulting in neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly or epilepsy,” Chandel said. “This led us to examine whether L-2HG could link mitochondrial dysfunction to neurological pathologies.”
Collaborating with co-corresponding author Joe Bateman, PhD, reader in Molecular Neuroscience at King’s College London, the investigators produced flies modeling mitochondrial dysfunction, finding a steady increase of L-2GH along with neurological symptoms. When they lowered L-2GH in these mitochondrial-deficient flies, the neurological symptoms disappeared and the flies were able to move normally again.
“This causally linked mitochondrial dysfunction to neuronal impairment by accumulation of L-2HG,” Chandel said.
Now, Chandel is planning to repeat these experiments in mice, testing whether L-2GH reduction can ameliorate mitochondrial dysfunction-induced neurological pathologies in mice.
“If L-2HG is a link between mitochondrial dysfunction and neurological pathologies, then it opens the possibility in a variety of diseases including Leigh Syndrome and Parkinson’s disease,” Chandel said.
Gregory McElroy, a fifth-year student in the Medical Scientist Training Program, was a co-author of the study.
This study was supported by National Institutes of Health grants AG049665-04 and T32CA9560-32.
