Senescent Hepatocytes in Decompensated Liver Show Reduced UPRMT and Its Key Player, CLPP, Attenuates Senescence In Vitro

Abstract

Background and Aims Non-dividing hepatocytes in end-stage liver disease indicates permanent growth arrest similar to senescence. Identifying senescence in vivo is often challenging and mechanisms inhibiting senescence are poorly understood. In lower organisms mitochondrial unfolded protein response (UPR MT ) helps in increasing longevity; however, its role in senescence and liver disease is poorly understood. Aim of this study was to identify hepatocyte senescence and the role of UPR MT in cryptogenic cirrhosis. Methods Doxorubicin was used to induce senescence in non-neoplastic hepatocytes (PH5CH8) and hepatoma cells (HepG2 and Huh7). Senescence-associated markers and unfolded protein response was evaluated by fluorescence microscopy, immunoblotting and gene expression. Explants/biopsies from normal, fibrosis, compensated and decompensated cirrhosis without any known etiology were examined for presence of senescence and UPR MT by immunohistochemistry and gene expression. Results Accumulation of senescent hepatocytes in cryptogenic cirrhosis was associated with reduced proliferation, increased expression of γH2AX and p21, together with loss of LaminB1. Dysfunctional mitochondria and compromised UPR MT were key features of senescent hepatocytes both in vitro and also in decompensated cirrhosis. Intriguingly, compensated cirrhotic liver mounted strong UPR MT , with high levels of mitochondrial protease, CLPP. Overexpression of CLPP inhibited senescence in vitro , by reducing mitochondrial ROS and altering oxygen consumption. Conclusions Our results implicate a role of hepatocyte senescence in cryptogenic cirrhosis together with a crucial role of UPR MT in preventing hepatocyte senescence. A compromised UPR MT may shift the fate of cirrhotic liver toward decompensation by exaggerating hepatocyte senescence. Restoring CLPP levels at least in cell culture appears as a promising strategy in mitohormesis, thereby, preventing senescence and possibly improving hepatocyte function.

Regeneration in acute-on-chronic liver failure – the phantom lost its camouflage

“…Chronic liver injury reduced the proliferative response of hepatocytes due to a predominant STAT1 activation, whereas control animals showed an IL6-STAT3-mediated proliferative effect. That is not entirely surprising as the aforementioned human studies, 5,6 as well as pre-clinical studies focussing on the effect of TGFb1, have already proposed that cirrhosis negatively modulates liver tissues' regenerative capacities. 17 Importantly, the acute hepatotoxic injury with CCl 4 , despite limiting regeneration and inducing a severe liver injury, did not impair survival or long-term recovery.…”

“…4 However, profound scientific evidence validating this hypothesis as well as an exploration of the underlying molecular mechanisms were lacking. Two recent studies in patients with acutely decompensated liver cirrhosis 5 and ACLF 6 showed that hepatocyte proliferation (Ki67), which is the major regenerative response after mild to moderate injury, was abrogated in end-stage liver disease. 6 However, these descriptive studies could not provide information about influencing factors or mechanisms.…”

Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP+ in human SH-SY5Y neuroblastoma cells

“…We speculate whether the YME1L1 transcription mRNA encoded by the nuclear genome is somehow increased by PGC-1α and is transported to the mitochondria for extensive expression, which remains to be further confirmed. The mitochondrial matrix protease Clp family consists of ClpAP, ClpCP, ClpEP, ClpXP and ClpYQ, which exist in the mitochondria of various prokaryotes and eukaryotes, as well as in the chloroplasts of algae and plant cells 49 . The active two-chain proteases are complex compounds consisting of a peptidase subunit (CLPP or ClpQ).…”

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

“…Due to these reasons, hepatocyte proliferation rates drop significantly during the stage of liver cirrhosis due to pathological adaption to stress. 104,105 Infected hepatocytes can manage the stress response through the induction of ISR that promotes the transcription of numerous genes for cell survival. 106 The significant reduction of hepatocyte proliferation in liver cirrhosis could activate stem cell compartment through epigenetic programming.…”