Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension

Zhou, Ben; Kreuzer, Johannes; Kumsta, Caroline; Wu, Lianfeng; Kamer, Kimberli J.; Cedillo, Lucydalila; Zhang, Yuyao; Li, Sainan; Kacergis, Michael C.; Webster, Christopher M.; Fejes-Tóth, Géza; Náray-Fejes-Tóth, Anikó; Das, Sudeshna; Hansen, Malene; Haas, Wilhelm; Soukas, Alexander A.

doi:10.1016/j.cell.2019.02.013

Cited by 142 publications

(160 citation statements)

References 61 publications

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“…We quantified autophagy immediately after the reproductive period (day 5), when LGG-1 puncta are more obvious. sgk-1 mutants showed an enhanced autophagy signal compared to wild type animals (Figure 5A), as previously described in worms [35, 38]. While depletion of the PHB complex significantly increased LGG-1 puncta in otherwise wild type worms, no additive effect was observed in sgk-1 mutants upon phb-1 depletion (Figure 5A).…”

Section: Resultssupporting

confidence: 85%

“…We observed swollen and bigger mitochondria in sgk-1 mutants as compared to wild type worms in all tissues analyzed (hypodermis, muscle and intestine) at both, day one and day five of adulthood (Figure 1B and Figure S1, respectively). No obvious mitochondrial fragmentation or severe cristae defects in the intestine could be observed in the TEM sections analyzed, as previously described [35].…”

Section: Resultssupporting

confidence: 61%

“…In C. elegans , loss of function of SGK-1 causes a delay in development [33] as well as reduced brood and body size [31]. These phenotypes are consistent with phenotypes observed in mitochondrial mutants [37] and mitochondrial fragmentation has been reported upon sgk-1 depletion in muscle [38] and intestine [35]. In addition, worms lacking the TORC2 component RICT-1 or the downstream kinase SGK-1, have an induced mitochondrial unfolded protein response (UPR mt ) [14].…”

Section: Resultssupporting

confidence: 60%

“…SGK-1 has been shown to modulate autophagy both via induction and blockage of autophagy [27-29, 35, 92, 93] and we observed an accumulation of abnormal autophagosomes in sgk-1 mutants (Figure 4A and Figure S7). Thus, we analyzed the autophagic state in sgk-1 mutants in the presence and in the absence of the PHB complex.…”

Section: Resultsmentioning

confidence: 79%

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Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

Hernando‐Rodríguez

Pérez-Jiménez

Rodríguez-Palero

et al. 2019

Preprint

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13 14 -2 -Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar 15 effect on lifespan. While PHB depletion shortens lifespan of wild type animals, it 16 enhances longevity of a plethora of metabolically compromised mutants, 17 including target of rapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Here, 18 we show that sgk-1 mutants have impaired mitochondrial homeostasis, 19 lipogenesis, yolk formation and autophagy flux due to alterations in membrane 20 lipid and sterol homeostasis. Remarkably, all these features are suppressed by 21 PHB depletion. Lifespan analysis shows that autophagy and the mitochondrial 22 unfolded protein response (UPR mt ), but not mitophagy, are required for the 23 enhanced longevity caused by PHB depletion in sgk-1 mutants. We hypothesize 24 that UPR mt induction upon PHB depletion extends lifespan of sgk-1 mutants 25 through autophagy. Our results strongly suggest that PHB depletion suppresses 26 the autophagy defects of sgk-1 mutants by altering membrane lipid composition 27 at ER-mitochondria contact sites, where TORC2 localizes. 28 29 93 mitochondria-associated endoplasmic reticulum (ER) membranes (MAM).94 95 -6 - Results 96Prohibitin depletion suppresses the altered mitochondrial structure and 97 function of sgk-1 mutants 98In C. elegans, loss of function of SGK-1 causes a delay in development (Jones et al., 992009) as well as reduced brood and body size (Soukas et al., 2009). These phenotypes 100 are consistent with phenotypes observed in mitochondrial mutants (Dillin et al., 2002). In 101 addition, worms lacking the TORC2 component RICT-1 or the downstream kinase SGK-102 1, have an induced mitochondrial unfolded protein response (UPR mt ) (Gatsi et al., 2014). 103We analyzed whether mitophagy, another mitochondrial quality control mechanism, 104 might be activated in sgk-1 deletion mutants using a mitophagy reporter based on PINK-105 1 protein (Kirienko et al., 2015). PINK-1 is a serine threonine protein kinase that, when 106 mitochondria are depolarized, accumulates in the outer mitochondrial membrane and 107 targets mitochondria for selective autophagy (Narendra and Youle, 2011; Palikaras et 108 al., 2015). We observed that depletion of sgk-1 increased PINK-1 protein levels ( Figure 109 1A). Similarly, PINK-1 protein levels increased upon depletion of phb-1 or atfs-1, the key 110 UPR mt regulator ( Figure 1A), confirming that sgk-1 mutants suffer from mitochondrial 111 stress. 112To better define the mitochondrial defect of sgk-1 deletion mutants we performed 113 transmission electron microscopy (TEM) analysis. Mitochondria in sgk-1 mutants were 114 swollen, and bigger compared to wild type worms in all tissues analyzed (hypodermis, 115 muscle and intestine) at both, day one and day five of adulthood ( Figure 1B and Figure 116 S1A, respectively). In contrast to previous observations (Zhou et al., 2019), no obvious 117 mitochondrial fragmentation or severe cristae defects in the intestine were observed in 118 the TEM sections analyzed. 119-7 -To ...

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Section: Resultssupporting

confidence: 85%

Section: Resultssupporting

confidence: 61%

Section: Resultssupporting

confidence: 60%

Section: Resultsmentioning

confidence: 79%

See 2 more Smart Citations

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

Hernando‐Rodríguez

Pérez-Jiménez

Rodríguez-Palero

et al. 2019

Preprint

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“…Unfortunately, evidence based-treatment for tackling liver injury is so far unavailable in clinical settings. Moreover, efforts to ameliorate the injury of hepatocytes by regulating their complications, such as intracellular oxidative stress, protein aggregates, and dysfunctional organelles, are far from satisfactory [5][6][7][8]. Thus, it is of immediate significance to explore effective pharmacological antidotes and strategies for liver injury treatment.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Chen

Zai

Fan

et al. 2020

Preprint

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AbstractInterleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.Graphical AbstractOur works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights.

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Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy

Zhang

Wang

et al. 2021

Advanced Science

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Cardiac hypertrophy is a pivotal pathophysiological step of various cardiovascular diseases, which eventually leads to heart failure and death. Extracts of Rhodiola species (Ext.R), a class of commonly used medicinal herbs in Europe and East Asia, can attenuate cardiac hypertrophy both in vitro and in vivo. Serum/glucocorticoid regulated kinase 1 (SGK1) is identified as a potential target of Ext. R. By mass spectrometry‐based kinase inhibitory assay, herbacetin (HBT) from Ext.R is identified as a novel SGK1 inhibitor with IC50 of 752 nmol. Thermal shift assay, KINOMEscan in vitro assay combined with molecular docking proves a direct binding between HBT and SGK1. Site‐specific mutation of Asp177 in SGK1 completely ablates the inhibitory activity of HBT. The presence of OH groups at the C‐3, C‐8, C‐4’ positions of flavonoids is suggested to be favorable for the inhibition of SGK1 activity. Finally, HBT significantly suppresses cardiomyocyte hypertrophy in vitro and in vivo, reduces reactive oxygen species (ROS) synthesis and calcium accumulation. HBT decreases phosphorylation of SGK1 and regulates its downstream forkhead box protein O1 (FoxO1) signaling pathway. Taken together, the findings suggest that a panel of flavonoids structurally related to HBT may be novel leads for developing new therapeutics against cardiac hypertrophy.

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Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension

Cited by 142 publications

References 61 publications

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy

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