SIRT3 Activation by Dihydromyricetin Suppresses Chondrocytes Degeneration via Maintaining Mitochondrial Homeostasis

Abstract

Mitochondrial dysfunction is an important contributor to the development of osteoarthritis (OA). Sirtuin 3 (SIRT3) regulates diverse mitochondrial proteins to maintain mitochondrial homeostasis, and dihydromyricetin (DHM) is reported as a potential SIRT3 activator. This study aims to explore the relevance of SIRT3 and OA, as well as the therapeutic effects of DHM on mitochondrial homeostasis in TNF-α-treated chondrocytes. The relationship between SIRT3 and OA was confirmed by detecting SIRT3 level in vitro and in vivo. Mitochondrial dysfunction was evaluated in chondrocytes with or without SIRT3 knockdown. Furthermore, the effects of DHM on mitochondrial homeostasis were performed in TNF-α-treated rat chondrocytes in vitro. In this study, our results showed that the SIRT3 level was decreased in mouse OA cartilage, corresponding to the reduced SIRT3 level in TNF-α-treated chondrocytes in vitro. SIRT3 knockdown induced mitochondrial dysfunction in chondrocytes. Moreover, our study demonstrated that DHM might activate SIRT3 to protect rat chondrocytes from TNF-α-induced degeneration and protective effects of DHM on mitochondrial homeostasis in chondrocytes attributed to enhanced SIRT3. Collectively, SIRT3 deficiency is implicated in OA development and DHM exerts anti-degeneration effect by maintaining mitochondrial homeostasis via a SIRT3-dependent manner in chondrocytes.

RETRACTED ARTICLE: Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis

“…This conclusion seems to oppose our observations. Thereby, our data, combined with the previous studies (Wang et al 2018a), support Sirt3 having multiple effects on mitochondrial stress and its potential functions depend on different cell types and a cellspecific context. Although our present study presents a new signaling pathway responsible for tongue cancer cell death, additional investigations using animal studies or human samples are needed to validate our concept and help transform basic research findings into clinical application.…”

“…Increased Fis1 expression triggered mitochondrial fission that exacerbated mitochondrial damage, ultimately initiating the mitochondriadependent apoptosis pathway in tongue cancer. Notably, a previous study has found that Sirt3 activation promotes Fis1 upregulation in the development of osteoarthritis (Wang et al 2018a). This conclusion seems to oppose our observations.…”

The Link between Chronic Stress and Accelerated Aging

“…Among SIRT3 activators, dihydromyricetin and honokiol were tested in various conditions related to mitochondrial functional impairments. Dihydromyricetin was shown to suppress chondrocyte degeneration in osteoarthritis [63]. Honokiol was reported to activate SIRT3 in a study dedicated to the treatment of intervertebral disc degeneration [64].…”

Improvement of cognitive and motor performance with mitotherapy in aged mice

“…Differently from nuclear DNA, the mtDNA lacks damage-repair mechanisms, and the mutations are susceptibility to accumulate. A recent study identified that the onset of aging symptoms would be determined by the ratio of mutant to wild-type mtDNA, with a typical threshold effect [19], and thus the mice with a high mutant ratio of mtDNA exhibit advanced aging phenotypes. Although aging-related mtDNA mutation is regarded as incurable and has to wait for the development of genome editing techniques, the supplement of healthy mitochondria will have great promise to decrease the mutant ratio of mtDNA and then slow down the aging phenotypes.…”