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Role of mitochondrial dysfunction in neurodegenerative aspects of multiple sclerosis

The aim of this project is to define the role of mitochondrial dysfunction in neurodegenerative aspects of multiple sclerosis (MS). Classically, MS has been considered primarily an inflammatory disease. As a result, much effort has gone into developing therapies to control the pernicious immune response in MS. However, over the past decade accumulating evidence indicates that MS is more complicated than earlier believed and has established the importance of to axonal injury as primarily responsible for the irreversible disability that occurs in afflicted individuals. Although the mechanisms are incompletely understood, one reasonable scenario proposes that neurodegenerative aspects of MS stem from a cascade of ionic imbalances involving mitochondrial dysfunction, concomitant deficits in cellular energy supply, mitochondrial Ca2+ overload and corresponding increases in the generation of reactive oxygen species (ROS).

Forte project: mitochondrial dysfunction in neurodegenerative aspects of multiple sclerosisUsing a mouse model of MS, our recent work has pointed to a specific mitochondrial protein controlling the mitochondrion's ability to release Ca2+ as critically involved in the axonal degeneration occurring in this disease. This work is the first to directly implicate mitochondria, and their role in cellular Ca2+ homeostatic networks, in a key aspect of the pathogenesis associated with MS. Future work will be directed by our overall hypothesis predicting that enhancing ability of axonal mitochondria to sequester Ca2+ in response to Ca2+ overload delays mitochondrial dysfunction leading to neurodegenerative aspects of MS. Experiments evaluating this idea will rest in large part on the use of genetic strategies available in mice to test the role of proteins suspected to be involved in regulating mitochondrial Ca2+ homeostasis in pathways leading to axonal destruction in mouse models of MS. These genetic studies will be complemented by live cell imaging to establish, for example, whether mitochondria missing specific proteins can preserve function in the face of elevated Ca2+ levels which would normally lead to the mitochondrial dysfunction and release of cell death activators. In the long term, our hope is that this work will lead to the identification of novel targets for therapeutic intervention, since effective management of this disease will require treatments that slow the pathogenic inflammatory response as well as neuroprotective strategies that reduce axonal damage.


Recent Publications

Šileikytė J, Blachly-Dyson E, Sewell R, Ricchelli R, Bernardi P, Forte M. (2014) The peripheral benzodiazepine receptor (TSPO) plays no role in the formation or regulation of the mitochondrial permeablity transition pore. J. Biol. Chem. 289: 13769-13781.

Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Glick G, Petronilli V, Zoratti M, Szabó I, Lippe G, Forte M, Bernardi P. (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc. Nat. Acad. Sci. U.S.A. 110: 5887-5892.

Su K, Bourdette D, Forte M. (2013) Mitochondrial dysfunction and neurodegeneration in multiple sclerosis through p66ShcA. Front. Physiol. 4: 169-179.

Barsukova A, Komarov A, Hajnóczky G, Bernardi P, Bourdette D, Forte M. (2011) Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons. Eur. J. Neurosci. 33: 831-842.