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Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics

Being an assembly of protein machines, cells depend on adequate supply of energetic molecules for retaining their homeodynamics. Consequently, mitochondria functionality is ensured by quality control systems and mitochondrial dynamics (fusion/fission). Similarly, proteome stability is maintained by...

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Autores principales: Gumeni, Sentiljana, Evangelakou, Zoi, Tsakiri, Eleni N., Scorrano, Luca, Trougakos, Ioannis P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536731/
https://www.ncbi.nlm.nih.gov/pubmed/31132524
http://dx.doi.org/10.1016/j.redox.2019.101219
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author Gumeni, Sentiljana
Evangelakou, Zoi
Tsakiri, Eleni N.
Scorrano, Luca
Trougakos, Ioannis P.
author_facet Gumeni, Sentiljana
Evangelakou, Zoi
Tsakiri, Eleni N.
Scorrano, Luca
Trougakos, Ioannis P.
author_sort Gumeni, Sentiljana
collection PubMed
description Being an assembly of protein machines, cells depend on adequate supply of energetic molecules for retaining their homeodynamics. Consequently, mitochondria functionality is ensured by quality control systems and mitochondrial dynamics (fusion/fission). Similarly, proteome stability is maintained by the machineries of the proteostasis network. We report here that reduced mitochondrial fusion rates in Drosophila caused developmental lethality or if induced in the adult accelerated aging. Imbalanced mitochondrial dynamics were tolerable for various periods in young flies, where they caused oxidative stress and proteome instability that mobilized Nrf2 and foxo to upregulate cytoprotective antioxidant/proteostatic modules. Consistently, proteasome inhibition or Nrf2, foxo knock down in young flies exaggerated perturbed mitochondrial dynamics toxicity. Neither Nrf2 overexpression (with concomitant proteasome activation) nor Atg8a upregulation suppressed the deregulated mitochondrial dynamics toxicity, which was mildly mitigated by antioxidants. Thus, despite extensive functional wiring of mitostatic and antioxidant/proteostatic modules, sustained loss-of mitostasis exhausts adaptation responses triggering premature aging.
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spelling pubmed-65367312019-05-30 Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics Gumeni, Sentiljana Evangelakou, Zoi Tsakiri, Eleni N. Scorrano, Luca Trougakos, Ioannis P. Redox Biol Research Paper Being an assembly of protein machines, cells depend on adequate supply of energetic molecules for retaining their homeodynamics. Consequently, mitochondria functionality is ensured by quality control systems and mitochondrial dynamics (fusion/fission). Similarly, proteome stability is maintained by the machineries of the proteostasis network. We report here that reduced mitochondrial fusion rates in Drosophila caused developmental lethality or if induced in the adult accelerated aging. Imbalanced mitochondrial dynamics were tolerable for various periods in young flies, where they caused oxidative stress and proteome instability that mobilized Nrf2 and foxo to upregulate cytoprotective antioxidant/proteostatic modules. Consistently, proteasome inhibition or Nrf2, foxo knock down in young flies exaggerated perturbed mitochondrial dynamics toxicity. Neither Nrf2 overexpression (with concomitant proteasome activation) nor Atg8a upregulation suppressed the deregulated mitochondrial dynamics toxicity, which was mildly mitigated by antioxidants. Thus, despite extensive functional wiring of mitostatic and antioxidant/proteostatic modules, sustained loss-of mitostasis exhausts adaptation responses triggering premature aging. Elsevier 2019-05-17 /pmc/articles/PMC6536731/ /pubmed/31132524 http://dx.doi.org/10.1016/j.redox.2019.101219 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Gumeni, Sentiljana
Evangelakou, Zoi
Tsakiri, Eleni N.
Scorrano, Luca
Trougakos, Ioannis P.
Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics
title Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics
title_full Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics
title_fullStr Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics
title_full_unstemmed Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics
title_short Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics
title_sort functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536731/
https://www.ncbi.nlm.nih.gov/pubmed/31132524
http://dx.doi.org/10.1016/j.redox.2019.101219
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