The Mitochondrial Unfolded Protein Response: A Hinge Between Healthy and Pathological Aging.

Francisco Muñoz-Carvajal,Mario Sanhueza

doi:10.3389/fnagi.2020.581849

Abstract

Aging is the time-dependent functional decline that increases the vulnerability to different forms of stress, constituting the major risk factor for the development of neurodegenerative diseases. Dysfunctional mitochondria significantly contribute to aging phenotypes, accumulating particularly in post-mitotic cells, including neurons. To cope with deleterious effects, mitochondria feature different mechanisms for quality control. One such mechanism is the mitochondrial unfolded protein response (UPRMT), which corresponds to the transcriptional activation of mitochondrial chaperones, proteases, and antioxidant enzymes to repair defective mitochondria. Transcription of target UPRMT genes is epigenetically regulated by Histone 3-specific methylation. Age-dependency of this regulation could explain a differential UPRMT activity in early developmental stages or aged organisms. At the same time, precise tuning of mitochondrial stress responses is crucial for maintaining neuronal homeostasis. However, compared to other mitochondrial and stress response programs, the role of UPRMT in neurodegenerative disease is barely understood and studies in this topic are just emerging. In this review, we document the reported evidence characterizing the evolutionarily conserved regulation of the UPRMT and summarize the recent advances in understanding the role of the pathway in neurodegenerative diseases and aging.

Highlights

Reviewed by: Karen Schmitt, Central Institute of Mental Health (ZI), Germany Merja Jaronen, University of Eastern Finland, Finland
Known activators of UPRMT include the impairment of the Electron Transport Chain (ETC), alteration of mitochondrial dynamics, accumulation of unfolded proteins, deletion of mitochondrial DNA, inhibition of mitochondrial chaperones or proteases, and the increase of reactive oxygen species (ROS) levels (Nargund et al, 2012; Pimenta de Castro et al, 2012; Runkel et al, 2013; Qureshi et al, 2017)
Despite the mechanisms underlying the UPRMT are less understood than endoplasmic reticulum UPR (Hetz et al, 2020), this mitochondrial stress pathway is emerging as an important response that guarantees the organelle function

Summary

UPRMT MACHINERY AND MITOCHONDRIAL HOMEOSTASIS REGULATION

Mitochondria are the main energy producers within the cell and the coordinators of several pathways that control essential metabolites, which include ATP and NAD+, and acetyl-CoA and S-adenosyl methionine for protein acetylation and methylation, respectively (Teperino et al, 2010; Menzies et al, 2016). This cascade increases the transcription of protease HTRA2 and the mitochondrial biogenesis regulator NFR1, which translates in an increased proteasome activity independent of activation of the UPRMT-ATF5 axis (Table 1, Papa and Germain, 2011). The UPRMTSIRT3 axis has been validated in worms and mammalian cells, supporting the high evolutionary conservation of the pathway (Mouchiroud et al, 2013) Both ERαand SIRT3-UPRMT axes work independently of CHOP (Papa and Germain, 2014), upholding the idea of three parallel paths coordinating the same stress response (Figure 1). This homeostatic regulation is important in post-mitotic cells such as neurons

THE ROLE AND REGULATION OF UPRMT IN AGING

UPRMT IN AGING NEURONS AND NEURODEGENERATIVE DISEASES

FUTURE PERSPECTIVES