Mitochondrial dysfunction contributes to neurodegenerative disorders, and improvement of mitochondrial bioenergetics may ameliorate neuronal and synaptic dysfunction. Parkinson's Disease (PD) is the second most prevalent neurodegenerative disease, characterized clinically by loss of normal motor system control and by defects in initiation and inhibition of motor and other nervous system programs. Pathologically, the disorder is characterized by loss of dopaminergic neurons within the substantia nigra pars compacta. Studies show that inhibitors of mitochondrial electron transport and of mitochondrial DNA replication predispose to the onset of PD. Familial disorders account for approximately 10% of this disorder and inform on sporadic disease. Several mutations in the gene for the protein DJ1 (PARK7) are associated with early-onset familial PD but the function of DJ1 has been incompletely understood. DJ1 mutant animals show increased sensitivity to neuronal toxins;DJ1 is required in different species for normal life span, intact motor function and resistance to neuronal oxidative damage. Mitochondria are implicated in mutant DJ1 dysfunction;DJ1 localizes to mitochondria and DJ1 mutant mitochondria have decreased ability to make ATP and abnormal respiration. DJ1 mutant mitochondria are sensitive to mitochondrial permeability transition (mPT), one hallmark of cell death, and mitochondria demonstrate abnormally high state 4 respiration, indicative of a leaky mitochondrial inner membrane. We hypothesize that DJ1 is required for the generation of normal respiratory coupling. Our preliminary studies have suggested that DJ1 is necessary for mitochondrial coupling: It binds to the mitochondrial F1/FO ATP synthase and inhibits a novel leak conductance channel that we have discovered within the ATP synthase c-subunit ring. In this application, we will determine the protein binding site for DJ1 in mammalian mitochondria, delineate pathological and physiological conditions under which DJ1 translocates to mitochondria, determine if DJ1 influences mitochondrial coupling (by regulating a newly described c-subunit leak conductance pore) and determine in mouse models if functional deficiency of DJ1 contributes to neurodegenerative metabolic stress, pathological permeability transition (PT) and cell death.
Parkinson's Disease (PD) is the second most prevalent neurodegenerative disease, characterized clinically loss of normal motor system control. Mitochondrial dysfunction contributes to PD. Familial disorders account for approximately 10% of this disorder and inform on sporadic disease. We hypothesize that PD familial mutant DJ1gene causes metabolic compromise of mitochondria and predisposes to untimely neuronal dysfunction and demise.
|Mnatsakanyan, Nelli; Beutner, Gisela; Porter, George A et al. (2017) Physiological roles of the mitochondrial permeability transition pore. J Bioenerg Biomembr 49:13-25|
|Jonas, Elizabeth (2016) The MIFstep in parthanatos. Science 354:36-37|
|Alavian, Kambiz N; Dworetzky, Steven I; Bonanni, Laura et al. (2015) The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole. Mol Pharmacol 87:1-8|
|Licznerski, Pawel; Duric, Vanja; Banasr, Mounira et al. (2015) Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress. PLoS Biol 13:e1002282|
|Park, Han-A; Licznerski, Pawel; Alavian, Kambiz N et al. (2015) Bcl-xL is necessary for neurite outgrowth in hippocampal neurons. Antioxid Redox Signal 22:93-108|
|Jonas, Elizabeth A; Porter Jr, George A; Beutner, Gisela et al. (2015) Cell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F(1)F(O) ATP synthase. Pharmacol Res 99:382-92|
|Alavian, Kambiz N; Beutner, Gisela; Lazrove, Emma et al. (2014) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 111:10580-5|
|Jonas, Elizabeth A (2014) Impaired import: how huntingtin harms. Nat Neurosci 17:747-9|