Mitigating peroxynitrite mediated mitochondrial dysfunction in aged rat brain by mitochondria-targeted antioxidant MitoQ
Although reactive oxygen species mediated oxidative stress is a well-documented mechanism of aging, recent evidences indicate involvement of nitrosative stress in the same. As mitochondrial dysfunction is considered as one of the primary features of aging, the present study was designed to understand the involvement of nitrosative stress by studying the impact of a mitochondria-targeted antioxidant MitoQ, a peroxynitrite (ONOO−) scavenger, on mitochondrial functions. Four groups of rats were included in this study: Group I: Young—6 months (-MitoQ), Group II: Aged—22 months (− MitoQ), Group III: Young—6 months (+ MitoQ), Group IV: Aged—22 months (+ MitoQ). The rats belonging to group III and IV were treated with oral administration of MitoQ (500 μM) daily through drinking water for 5 weeks. MitoQ efficiently suppressed synaptosomal lipid peroxidation and protein oxidation accompanied by diminution of nitrite production and protein bound 3-nitrotyrosine. MitoQ normalized enhanced caspase 3 and 9 activities in aged rat brains and efficiently reversed ONOO− mediated mitochondrial complex I and IV inhibition, restored mitochondrial ATP production and lowered mitochondrial membrane potential loss. To ascertain these findings, a mitochondrial in vitro model (iron/ascorbate) was used involving different free radical scavengers and anti-oxidants. MitoQ provided better protection compared to mercaptoethylguanidine, N-nitro-l-arginine-methyl ester and superoxide dismutase establishing the predominancy of ONOO− in the process compared to •NO and O 2 •− . These results clearly highlight the involvement of nitrosative stress in aging process with MitoQ having therapeutic potential to fight against ONOO− mediated aging deficits.
KeywordsMitochondrial electron transport chain MitoQ Aging Peroxynitrite Nitrosative stress
The authors thank Department of Zoology, Jhargram Raj College, West Bengal, India and Department of Zoology, University of Burdwan, West Bengal, India, Pin-741235 for providing permission and laboratory assistance for smooth running of the project. Our sincere thanks to Department of Zoology, Jhargram Raj College, West Bengal, India for funding this project work.
Compliance with ethical standards
Conflict of interest
The authors of this paper declare that there is no conflict of interest.
- Clark JB, Bates TE, Boakye P, Kuimov A, Land JM (1997) Investigation of mitochondrial defects in brain and skeletal muscle. In: Turner AJ, Bachelard HS (eds) Neurochemistry: A practical approach. Oxford University Press Inc., New York, pp 151–174Google Scholar
- Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS (2013) Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines. BMC Med 11:178CrossRefPubMedPubMedCentralGoogle Scholar
- Genrikhs EE, Stelmashook EV, Popova OV, Kapay NA, Korshunova GA, Sumbatyan NV, Skrebitsky VG, Skulachev VP, Isaev NK (2015) Mitochondria-targeted antioxidant SkQT1 decreases trauma-induced neurological deficit in rat and prevents amyloid-b-induced impairment of long-term potentiation in rat hippocampal slices. J Drug Target 23:347–352CrossRefPubMedGoogle Scholar
- Gow AJ, Farkouh CR, Munson DA, Posencheg MA, Ischiropoulos H (2004) Biological significance of nitric-oxide mediated protein modifications. Am J Physiol 287:L262–L268Google Scholar
- Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine, 3rd edn. Oxford University Press, New YorkGoogle Scholar
- James AM, Cocheme HM, Smith RA, Murphy MP (2005) Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem 280:21295–21312CrossRefPubMedGoogle Scholar
- Ljubuncic P, Gochman E, Reznick AZ (2010) Nitrosative stress in aging. Its importance and biological implications in NF-kB signaling. In: Bondy S, Maiese K (eds) Oxidative Stress in Applied Basic Research and Clinical Practice. Aging and Age-Related Disorders. Springer, Armstrong, pp 27–54Google Scholar
- Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O’Sullivan JD, Fung V, Smith RA, Murphy MP, Taylor KM, Protect Study Group (2010) A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease modifying therapy in Parkinson’s disease. Mov Disord 25:1670–1674CrossRefPubMedGoogle Scholar
- Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Fulop GA, Hertelendy P, Gautam T, Farkas E, Perz A, Rabinovitch PS, Sonntag WE, Csiszar A, Ungvari Z (2018) Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell. https://doi.org/10.1111/acel.12731 PubMedPubMedCentralGoogle Scholar
- Whittaker V (1972) The Synaptosome. In: Lajtha S (ed) Hand book of neurochemistry. Plenum Press, New York, pp 327–364Google Scholar