In Honor of Nobel Laureate Prof. M Stanley Whittingham
| DEVELOPMENT OF MITOCHONDRIA TARGETED THERAPEUTICS FOR NEURODEGENERATIVE DISEASES Eugenia Trushina1; Andrea Stojakovic1; Sergey Trushin1; Thi Kim Oanh Nguyen1; Mark Ostroot1; 1MAYO CLINIC, Rochester, United States; PAPER: 345/Oxidative/Plenary (Oral) OS SCHEDULED: 11:30/Wed. 29 Nov. 2023/Dreams 1 ABSTRACT: A decreased ability to maintain consistent energy production and a low level of oxidative stress in brain cells have been identified among the underlying factors for the development of various neurodegenerative conditions, such as Alzheimer's disease (AD). Mitochondria play a central role in maintaining energy homeostasis and generating reactive oxygen species in cells. Mitochondrial dysfunction is well documented in AD patients. However, recent evidence has revealed the important roles of mitochondria signaling in adapting to energy stress, promoting survival and function, and restoring energy levels. Mitochondria signaling coordinates several crucial cellular mechanisms, including maintaining energy balance, metabolic functions, autophagy, epigenetic modifications, regulating inflammation, providing antioxidant protection, and regulating cell death. Thus, harnessing mitochondrial signaling could represent a novel therapeutic strategy to improve and maintain multiple essential mechanisms of cell survival. We have developed small molecules that target mitochondria and mildly reduce the activity of mitochondrial complex I, resulting in the induction of mild energetic stress. This approach has proven effective in delaying the onset of AD in multiple transgenic mouse models and promoting healthy aging in wild-type mice [1-6]. The mechanism of action involves activating various neuroprotective mechanisms involved in adaptive stress response, which ultimately results in promoting health and longevity, and restoring mitochondria function and energy balance in the brain. References: [1] Zhang L, Zhang S, Maezawa I, Trushin S, Minhas P, Pinto M, Jin LW, Prasain K, Nguyen TD, Yamazaki Y et al: Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease. EBioMedicine 2015, 2(4):294-305.<br />[2] Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S et al: Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov 2020, 19(9):609-633<br />[3] Stojakovic A, Trushin S, Sheu A, Khalili L, Chang SY, Li X, Christensen T, Salisbury JL, Geroux RE, Gateno B et al: Partial inhibition of mitochondrial complex I ameliorates Alzheimer's disease pathology and cognition in APP/PS1 female mice. Commun Biol 2021, 4(1):61.<br />[4] Trushina E, Trushin S, Hasan MF: Mitochondrial complex I as a therapeutic target for Alzheimer's disease. Acta Pharm Sin B 2022, 12(2):483-495<br />[5] Stojakovic A, Chang SY, Nesbitt J, Pichurin NP, Ostroot MA, Aikawa T, Kanekiyo T, Trushina E: Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice. J Alzheimers Dis 2021, 79(1):335-353.<br />[6] Panes J, Nguyen tKO, Gao H, Christensen TA, Stojakovic A, Trushin S, Salisbury JL, Fuentealba J, Trushina E: Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice. Cells 2023, 12. |
