The research program in the Mitochondria and Neurodegeneration Unit (MNU) is focused on mechanisms of mitochondrial functional and structural regulation and the alterations that accompany primary mitochondrial encephalomyopathies and other neurodegenerative disorders, in which mitochondrial dysfunction is etiologically involved. Among the neurodegenerative diseases with mitochondrial involvement, a special emphasis is on amyotrophic lateral sclerosis (ALS). The MNU investigates mitochondrial functional and structural alterations in genetic forms of primary mitochondrial diseases and ALS, using both animal and cellular models and cells directly derived from patients. The overarching goals are to understand disease mechanisms, discover disease biomarkers, identify therapeutic targets and test novel therapeutic approaches. Major active lines of research are focused on bioenergetic alterations and other aspects of mitochondrial pathophysiology, including mitochondrial dynamics, mitochondrial quality control, calcium homeostasis, oxidative stress, the interactions between mitochondria and other organelles, and the role of estrogen receptors in modulating neuronal mitochondrial function in response to ischemic injury. Researchers in the MNU utilize diverse approaches and platforms, in vitro and in vivo, including patient-derived cells and mouse models of mitochondrial diseases, and neurodegeneration. Members of the MNU take advantage of a variety of tools to assess mitochondrial functions, such as mouse and cells models expressing genetically encoded reporters for live imaging, high-content imaging for cellular studies in primary patient cells and iPSC-derived neurons and glia, as well as immunocytochemical and ultrastructural studies ex vivo. Recent advancements have further expanded the scopes of the research in the MNU, as the field has come to the realization that mitochondrial dysfunction is not simply a bioenergetic problem. The implications of mitochondrial dysfunction are, in fact, much broader, strongly implicating many aspects of metabolism. The MNU is interested in the complex set of metabolic responses that underlie the mitochondrial integrated stress response and its maladaptive consequences, because maladaptive changes in metabolism in conditions of chronic mitochondrial dysfunction play crucial roles in neurodegenerative diseases.
Among recent accomplishments of the MNU are the discovery of: 1) a complete rewiring of glutamine-glutamate metabolism in cellular and animal models of mitochondrial diseases caused by respiratory chain deficiency (Cell Metab. 2018 May 1;27(5):1007-1025); 2) a powerful maladaptive mitochondrial integrated stress response in a novel knock in mouse model of mutations in the mitochondrial protein CHCHD10 associated with a mitochondrial syndrome characterized by FTD/ALS and myopathy (Acta Neuropathol. 2019 Jul;138(1):103-121); 3) a new subclass of ALS patients defined by metabolic alterations of the transsulfuration pathway (Neurobiology of Disease, Volume 144, October 2020, 105025); 4) a novel role of IGF1R and mTOR dysregulation in the toxicity of astrocytes towards motor neurons in the pathogenesis of familial ALS (Autophagy, 2021, in press).