SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis

Abstract

Constitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts. Moreover, hexafluoro attenuated mitochondrial and cytosolic reactive oxygen species (ROS) accumulation in TGF-β-treated fibroblasts. Remarkably, we found that the expression of SIRT3 was significantly reduced in SSc skin biopsies and explanted fibroblasts, and was suppressed by TGF-β treatment in normal fibroblasts. Moreover, tissue levels of acetylated MnSOD, a sensitive marker of reduced SIRT3 activity, were dramatically enhanced in lesional skin and lung biopsies from SSc patients. Mice treated with hexafluoro showed substantial attenuation of bleomycin-induced fibrosis in the lung and skin. Our findings reveal a cell-autonomous function for SIRT3 in modulating fibrotic responses, and demonstrate the ability of a novel pharmacological SIRT3 agonist to attenuate fibrosis in vitro and in vivo. In light of the impaired expression and activity of SIRT3 associated with organ fibrosis in SSc, pharmacological approaches for augmenting SIRT3 might have therapeutic potential.

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…In concordance, SIRT3-deficient, aging mice were found to develop tissue fibrosis of multiple organs, including heart, liver, kidney, and lungs (87). In the lung, SIRT3 deficiency augmented pulmonary fibrosis after asbestos and bleomycin exposure (88,89), and SIRT3 expression is attenuated in skin and lung of systemic sclerosis patients (90). It is also proposed that SIRT3 modulates mtDNA damage by regulating 8-oxoguanine-DNA glycosylase-1 (OGG1) acetylation (91,92).…”

“…For instance, a transgenic mouse model of mitochondrial catalase mediates protection against asbestos, and bleomycin induced lung fibrosis associated with prevention of mitochondrial DNA damage (159). Hexafluoro, a novel honokiol derivative, has been shown to induce SIRT3 expression in lung fibroblasts and protect from TGF-β-mediated SIRT3 depletion and ameliorate bleomycin-induced lung fibrosis in mice (90). Our studies on mitochondria homeostasis have shown preferential mitophagy dysregulation, and alterations in fusion/fission dynamics are deregulated in the fibrotic lung.…”

Sirtuins and Accelerated Aging in Scleroderma

“…At the time of preparation of this review, there are only a handful of reports that have directly addressed the involvement of SIRTs in SSc [99–102, 111, 112, 121]. Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121].…”

“…Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121]. The prevailing message from these studies is that SIRTs play an antifibrotic role in SSc and engage in mutual negative feedback with the TGF-β signaling pathway, the most potent known driver of fibrosis.…”

“…The majority of studies have shown decreased SIRT expression in tissues and fibroblasts from patients with SSc compared to controls and in experimental fibrosis in mice [99–101, 111, 112, 121]. Decreases in SIRT1 were observed in fibrotic skin and dermal fibroblasts from patients with SSc [100, 101] and in peripheral blood mononuclear cells of SSc patients with pulmonary fibrosis compared to patients without fibrosis [99].…”