A recent Northwestern Medicine study may improve the understanding of mitochondrial dysfunction and its impact on the development of neurological diseases, according to findings published in Cell Metabolism.
The study, led by Greg McElroy, a sixth year student in the Medical Scientist Training Program (MSTP), also suggests that targeting mitochondrial complex I linked biology could be a promising therapeutic target for neurological diseases. Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, was senior author of the study.
The inner membrane of a cell’s mitochondria contains five multi-subunit complexes part of the election transport chain, which generates energy production by producing adenosine triphosphate (ATP) to drive various cell functions and drives the production of metabolites linked to the cell’s tricarboxylic acid cycle (TCA) to promote cell proliferation and growth.
Mitochondrial complex I plays an essential role in generating proton pumps for TCA cycle function and ATP production, as well as the regeneration of NAD+, a cofactor found in all living cells that carries electrons to drive cellular processes.
Previous work has shown that the development of neurological diseases such as Parkinson’s disease and Leigh Syndrome — a rare and severe neurological disorder most commonly seen in babies and young children — are linked to the dysfunction of mitochondrial complex I. But how the mitochondria complex I maintains brain health has remained unknown, according to Chandel.
For the current study, the investigators sought to determine which mitochondrial complex I function — ATP or NAD+ production — was dominant in protecting the brain from symptoms commonly found in patients with Leigh Syndrome, including inflammation, epilepsy and loss of motor control.
The team utilized mouse models of Leigh Syndrome where a subunit of complex I called NDUFS4 was mutated. In one group of mice, they inserted into the brain a yeast protein called NADH dehydrogenase (NDI1), which is able to replace only NAD+ regeneration in mitochondrial complex I but not the proton pumping function linked to ATP production.
Overall, NDI1 prolonged the lifespan of the mice and contributed to NAD+ regeneration, but not ATP production. NDI1 also eradicated both inflammation and epilepsy in the mice, but not poor motor function, according to Chandel.
“This tells you that the NAD+ regeneration is important to control inflammation, epilepsy, lifespan, and brain health, but you still need that little bit of ATP from complex I for motor function,” Chandel said. “That’s important because it shows what different aspects of mitochondria are important for different biological responses. It is possible that yeast NDI1 protein could be used as gene therapy for certain neurological disease where mitochondrial complex I is diminished.”
The findings also suggest greater therapeutic potential in targeting the biology of NAD+ to treat neurological diseases, according to Chandel, who noted that the team is currently using the same technique to evaluate mouse models of Parkinson’s disease.
Colleen Reczek, PhD, research assistant professor of Medicine in the Division of Pulmonary and Critical Care; Paul Reyfman, MD, ’18 MS, ’17 GME, assistant professor of Medicine in the Division of Pulmonary and Critical Care; Divakar Mithal, ’13 MD, ’11 PhD, ’15, ’18, ’19 GME,, instructor of Pediatrics in the Division of Neurology and Epilepsy; and Craig Horbinski, MD, PhD, director of Neuropathology in the Department of Pathology, were co-authors of the study. Chandel and Horbinski are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Chandel is also a member of Northwestern University’s Chemistry of Life Processes Institute.
This work was supported by National Institutes of Health grants NIH2PO1HL071643-11A1, NIH1R35CA197532-01, and NIH1- PO1AG049665-01; National Cancer Institute grant T32CA09560; National Heart, Lung, and Blood Institute grant T32HL076139-11and F32HL136111; the National Institute of Neurological Disorders and Stroke grants R25 NS070695, K08CA155764 and R01NS102669; and an American Thoracic Society/Boehringer Ingelheim Partner grant.
