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Toxicol In Vitro. 2020 Feb;62:104695. doi: 10.1016/j.tiv.2019.104695. Epub 2019 Oct 19.

LONP1 induction by SRT1720 attenuates mitochondrial dysfunction against high glucose induced neurotoxicity in PC12 cells.

Author information

1
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Balanagar, India.
2
Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
3
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Balanagar, India. Electronic address: ashutosh@niperhyd.ac.in.

Abstract

Neuropathies caused by mitochondrial dysfunction are the most common and serious impediment of high glucose (HG)-induced toxicity. We have previously reported mitoprotective potency of Sirtuin1 (Sirt1) in diabetic neuropathy (DN) via targeting mitochondrial dysfunction but its nuclear control over mitochondrial bioenergetics remains unknown. Here, we studied the effect of SRT1720; a small molecule activator of Sirt1 in attenuating the HG mediated mitochondrial dysfunction in differentiated rat pheochromocytoma (PC12) cells and aiming to determine (1) whether SRT1720 can improve mitochondrial function in HG exposed PC12 cells (2) if yes then this effect is dependent or independent of mitochondrial Lon protease (LONP1) (3) and whether silencing of LONP1 affects the mitochondrial function or not. HG (30 mM) exposed PC12 cells demonstrated reduced mitochondrial complex activities and oxygen consumption rate (OCR), decreased the expressions of Sirt1, peroxisome proliferator-activated receptor coactivator-1α (PGC1α), nuclear respiratory factor-2 (NRF2), LONP1 and ATP synthase c. SRT1720 treatment (4 μM) significantly reversed these effects in hyperglycemia insulted PC12 cells but silencing the expression of LONP1 impeded this effect of SRT1720 on mitochondrial complex activities, OCR and mitochondrial membrane potential. Based on these findings, we inferred that SRT1720 might improve mitochondrial function in HG induced mitochondrial dysfunction in PC12 cells via stimulation of Sirt1-LONP1 axis.

KEYWORDS:

Mitochondrial Lon protease; Mitochondrial function; SRT1720; Sirt1

PMID:
31639451
DOI:
10.1016/j.tiv.2019.104695

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