Mitochondrial proteostasis in the context of cellular and organismal health and aging

Moehle, Erica A.; Shen, Koning; Dillin, Andrew

doi:10.1074/jbc.tm117.000893

Cited by 149 publications

(119 citation statements)

References 156 publications

(145 reference statements)

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“…CEBPb, ATF4, and CHOP are also key activators of the mitochondrial unfolded protein response (mtUPR) (Higuchi-Sanabria et al, 2018;Moehle et al, 2018); however, we did not observe significant upregulation of mitochondrial proteases in the Mrps12 ep/ep mice, perhaps due to a simultaneous induction of systems that stabilize mitochondrial respiratory complexes, as we observed in these mice at 10 weeks of age. We and others have previously observed increased ATF4 and CHOP in mouse models with impaired mitochondrial translation (Rackham et al, 2016;Seiferling et al, 2016;Perks et al, 2018), and impaired mitochondrial translation can induce mtUPR in worms and mammalian cell culture (Houtkooper et al, 2013).…”

Section: Of 19contrasting

confidence: 71%

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

et al. 2019

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Translation fidelity is crucial for prokaryotes and eukaryotic nuclear‐encoded proteins; however, little is known about the role of mistranslation in mitochondria and its potential effects on metabolism. We generated yeast and mouse models with error‐prone and hyper‐accurate mitochondrial translation, and found that translation rate is more important than translational accuracy for cell function in mammals. Specifically, we found that mitochondrial mistranslation causes reduced overall mitochondrial translation and respiratory complex assembly rates. In mammals, this effect is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, this induced mitochondrial stress signaling, which enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression, and cell proliferation, and thereby normalizes metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting a mitochondrial stress response. Consequently, the rate of translation cannot be recovered and this leads to dilated cardiomyopathy in mice. In summary, our findings reveal mammalian‐specific signaling pathways that respond to changes in the fidelity of mitochondrial protein synthesis and affect metabolism.

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Section: Of 19contrasting

confidence: 71%

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

et al. 2019

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“…Mitochondrial stress signalling. The accumulation of unfolded proteins in the mitochondrial matrix drives a variant of the UPR (commonly referred to as UPR mt ), which resembles the UPR ER in its general organization -namely, the activation of a broad transcriptional response aimed at the restoration of mitochondrial proteostasis [69][70][71] . Although they share some signal transdu cers and effectors (see below), the UPR mt and the UPR ER should be considered as two distinct processes, not only because they respond to stress at two different cellular compartments but also because they have cellular, local and systemic consequences that only partially overlap 51,72 .…”

Section: Dendritic Cellsmentioning

confidence: 99%

Linking cellular stress responses to systemic homeostasis

Galluzzi

Yamazaki

Kroemer

2018

Nat Rev Mol Cell Biol

401

245

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| Mammalian cells respond to stress by activating mechanisms that support cellular functions and hence maintain microenvironmental and organismal homeostasis. Intracellular responses to stress, their regulation and their pathophysiological implications have been extensively studied. However, little is known about the signals that emanate from stressed cells to enable a coordinated adaptive response across tissues, organs and the whole organism. Considerable evidence has now accumulated indicating that the intracellular mechanisms that are activated in response to different stresses -which include the DNA damage response, the unfolded protein response, mitochondrial stress signalling and autophagy -as well as the mechanisms ensuring the proliferative inactivation or elimination of terminally damaged cells -such as cell senescence and regulated cell death -are all coupled with the generation of signals that elicit microenvironmental and/or systemic responses. These signals, which involve changes in the surface of stressed cells and/or the secretion of soluble factors or microvesicles, generally support systemic homeostasis but can also contribute to maladaptation and disease. *

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“…Since functional mitochondria are essential for homeostasis and survival of the HF epithelium and HF stem cells (at least in mice in vivo), continuous stimulation of PPAR‐γ by endogenous ligands may be required for the maintenance of HF energy metabolism, for intrafollicular PPAR‐γ expression and activity would then play an important role in human HF physiology. Moreover, given the central role of accumulating mitochondrial defects in tissue ageing, pharmacological stimulation of intrafollicular PPAR‐γ signalling is a plausible candidate strategy for improving the mitochondrial energy metabolism of ageing or stressed HFs.…”

Section: Ppar‐γ Signalling In Human Hair Follicle Physiologymentioning

confidence: 99%

“…given the central role of accumulating mitochondrial defects in tissue ageing, [116][117][118] pharmacological stimulation of intrafollicular PPAR-γ signalling is a plausible candidate strategy for improving the mitochondrial energy metabolism of ageing or stressed HFs.…”

Section: Ppa Rγ S I G Nalling In H Uman Hair Folli Cle Phys I Ologymentioning

confidence: 99%

PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

Ramot

Bertolini

Boboljova

et al. 2019

Experimental Dermatology

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Peroxisome proliferator‐activated receptors (PPARs) are abundantly expressed in human skin, with PPAR‐γ being the most intensively investigated isoform. In various ex vivo and in vivo models, PPAR‐γ‐mediated signalling has recently surfaced as an essential element of hair follicle (HF) development, growth and stem cell biology. Moreover, the availability of novel, topically applicable PPAR‐γ modulators with a favourable toxicological profile has extended the range of potential applications in clinical dermatology. In this review, we synthesize where this field currently stands and sketch promising future research avenues, focussing on the role of PPAR‐γ‐mediated signalling in the biology and pathology of human scalp HFs, with special emphasis on scarring alopecias such as lichen planopilaris and frontal fibrosing alopecia as model human epithelial stem cell diseases. In particular, we discuss whether and how pharmacological modulation of PPAR‐γ signalling may be employed for the management of hair growth disorders, for example, in scarring alopecia (by reducing HF inflammation as well as by promoting the survival and suppressing pathological epithelial‐mesenchymal transition of keratin 15 + epithelial stem cells in the bulge) and in hirsutism/hypertrichosis (by promoting catagen development). Moreover, we explore the potential role of PPAR‐γ in androgenetic alopecia, HF energy metabolism and HF ageing, and consider clinical perspectives that emanate from the limited data available on this so far. As this field of translational human hair research is still in its infancy, many open questions exist, for which we briefly delineate selected experimental approaches that promise to generate instructive answers in the near future.

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Mitochondrial proteostasis in the context of cellular and organismal health and aging

Cited by 149 publications

References 156 publications

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Linking cellular stress responses to systemic homeostasis

PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

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