scholarly journals Molecular Mechanisms and Regulation of Mammalian Mitophagy

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 38
Author(s):  
Vinay Choubey ◽  
Akbar Zeb ◽  
Allen Kaasik
Keyword(s):  
Quality Control ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Stress Protein ◽  
Antioxidant Defenses ◽  
Control Mechanisms ◽  
Mitochondrial Dna Damage ◽  
Cellular Environment ◽  
Rigorous Research ◽  
Functional Versatility

Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.

scholarly journals Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Courtney L Klaips ◽  
Megan L Hochstrasser ◽  
Christine R Langlois ◽  
Tricia R Serio
Keyword(s):  
Quality Control ◽  
Molecular Chaperone ◽  
Protein Misfolding ◽  
Elevated Temperatures ◽  
Control Factor ◽  
Control Mechanisms ◽  
Cellular Environment ◽  
Effective Activity ◽  
Spatial Quality

The proteostasis network has evolved to support protein folding under normal conditions and to expand this capacity in response to proteotoxic stresses. Nevertheless, many pathogenic states are associated with protein misfolding, revealing in vivo limitations on quality control mechanisms. One contributor to these limitations is the physical characteristics of misfolded proteins, as exemplified by amyloids, which are largely resistant to clearance. However, other limitations imposed by the cellular environment are poorly understood. To identify cell-based restrictions on proteostasis capacity, we determined the mechanism by which thermal stress cures the [PSI+]/Sup35 prion. Remarkably, Sup35 amyloid is disassembled at elevated temperatures by the molecular chaperone Hsp104. This process requires Hsp104 engagement with heat-induced non-prion aggregates in late cell-cycle stage cells, which promotes its asymmetric retention and thereby effective activity. Thus, cell division imposes a potent limitation on proteostasis capacity that can be bypassed by the spatial engagement of a quality control factor.

scholarly journals Microautophagy – distinct molecular mechanisms handle cargoes of many sizes

2020 ◽  
Vol 133 (17) ◽  
pp. jcs246322 ◽  
Author(s):  
Sebastian Schuck
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Snare Proteins ◽  
Metabolic Adaptation ◽  
The Core ◽  
Range Of Functions ◽  
Fusion Type ◽  
Functional Versatility

ABSTRACTAutophagy is fundamental for cell and organismal health. Two types of autophagy are conserved in eukaryotes: macroautophagy and microautophagy. During macroautophagy, autophagosomes deliver cytoplasmic constituents to endosomes or lysosomes, whereas during microautophagy lytic organelles take up cytoplasm directly. While macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become clear that microautophagy has a broad range of functions in biosynthetic transport, metabolic adaptation, organelle remodeling and quality control. This Review discusses the selective and non-selective microautophagic processes known in yeast, plants and animals. Based on the molecular mechanisms for the uptake of microautophagic cargo into lytic organelles, I propose to distinguish between fission-type microautophagy, which depends on ESCRT proteins, and fusion-type microautophagy, which requires the core autophagy machinery and SNARE proteins. Many questions remain to be explored, but the functional versatility and mechanistic diversity of microautophagy are beginning to emerge.

scholarly journals ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

2021 ◽  
Vol 8 ◽  
Author(s):  
Venturina Stagni ◽  
Alessandra Ferri ◽  
Claudia Cirotti ◽  
Daniela Barilà
Keyword(s):  
Cell Fate ◽  
Ataxia Telangiectasia ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Premature Aging ◽  
Ataxia Telangiectasia Mutated ◽  
Atm Kinase ◽  
Cellular Environment ◽  
Key Factor

Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.

scholarly journals Polyamines as Quality Control Metabolites Operating at the Post-Transcriptional Level

Plants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 109 ◽  
Author(s):  
Laetitia Poidevin ◽  
Dilek Unal ◽  
Borja Belda-Palazón ◽  
Alejandro Ferrando
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
Control Mechanisms ◽  
Physiological Functions ◽  
Nonsense Mediated Decay ◽  
Stop Codons ◽  
Ribosome Stalling ◽  
Molecular Functions

Plant polyamines (PAs) have been assigned a large number of physiological functions with unknown molecular mechanisms in many cases. Among the most abundant and studied polyamines, two of them, namely spermidine (Spd) and thermospermine (Tspm), share some molecular functions related to quality control pathways for tightly regulated mRNAs at the level of translation. In this review, we focus on the roles of Tspm and Spd to facilitate the translation of mRNAs containing upstream ORFs (uORFs), premature stop codons, and ribosome stalling sequences that may block translation, thus preventing their degradation by quality control mechanisms such as the nonsense-mediated decay pathway and possible interactions with other mRNA quality surveillance pathways.

scholarly journals The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

2009 ◽  
Vol 20 (15) ◽  
pp. 3459-3470 ◽  
Author(s):  
Viktoria Hessle ◽  
Petra Björk ◽  
Marcus Sokolowski ◽  
Ernesto González de Valdivia ◽  
Rebecca Silverstein ◽  
...  
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Mechanistic Model ◽  
Model Systems ◽  
Control Mechanisms ◽  
Hnrnp Proteins ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Transcription Sites ◽  
Mrna Binding

Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.

scholarly journals APE1/Ref-1 Interacts with NPM1 within Nucleoli and Plays a Role in the rRNA Quality Control Process

2009 ◽  
Vol 29 (7) ◽  
pp. 1834-1854 ◽  
Author(s):  
Carlo Vascotto ◽  
Damiano Fantini ◽  
Milena Romanello ◽  
Laura Cesaratto ◽  
Marta Deganuto ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rrna Synthesis ◽  
Control Mechanisms ◽  
Endonuclease Activity ◽  
Proteomic Approach ◽  
Quality Control Process

ABSTRACT APE1/Ref-1 (hereafter, APE1), a DNA repair enzyme and a transcriptional coactivator, is a vital protein in mammals. Its role in controlling cell growth and the molecular mechanisms that fine-tune its different cellular functions are still not known. By an unbiased proteomic approach, we have identified and characterized several novel APE1 partners which, unexpectedly, include a number of proteins involved in ribosome biogenesis and RNA processing. In particular, a novel interaction between nucleophosmin (NPM1) and APE1 was characterized. We observed that the 33 N-terminal residues of APE1 are required for stable interaction with the NPM1 oligomerization domain. As a consequence of the interaction with NPM1 and RNA, APE1 is localized within the nucleolus and this localization depends on cell cycle and active rRNA transcription. NPM1 stimulates APE1 endonuclease activity on abasic double-stranded DNA (dsDNA) but decreases APE1 endonuclease activity on abasic single-stranded RNA (ssRNA) by masking the N-terminal region of APE1 required for stable RNA binding. In APE1-knocked-down cells, pre-rRNA synthesis and rRNA processing were not affected but inability to remove 8-hydroxyguanine-containing rRNA upon oxidative stress, impaired translation, lower intracellular protein content, and decreased cell growth rate were found. Our data demonstrate that APE1 affects cell growth by directly acting on RNA quality control mechanisms, thus affecting gene expression through posttranscriptional mechanisms.

scholarly journals Mitophagy Eliminates the Accumulation of SARM1 on the Mitochondria, Alleviating Programmed Axon Death in Acrylamide Neuropathy

2022 ◽  
Author(s):  
Shuai Wang ◽  
Hui Yong ◽  
Cuiqin Zhang ◽  
Kang Kang ◽  
Mingxue Song ◽  
...  
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Biological Significance ◽  
Control Mechanisms ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Mitochondrial Localization ◽  
Mitochondrial Quality Control ◽  
Axon Loss

Abstract Sterile-α and toll/interleukin 1 receptor motif containing protein 1 (SARM1) is the central executioner of programmed axon death (Wallerian degeneration). Although it has been confirmed to have a mitochondrial targeting sequence and can bind to and stabilize PINK1 on mitochondria, the biological significance for mitochondrial localization of SARM1 is still unclear. The relationship between mitochondrial quality control mechanisms and programmed axon death also needs to be clarified. Chronic acrylamide (ACR) intoxication cause typical pathology of axon degeneration involving early axon loss. Here, we demonstrated that the SARM1 dependent Wallerian axon self-destruction pathway was activated following ACR intoxication. Moreover, increased SARM1 was observed on the mitochondria, which interfered with the mitochondrial quality control mechanisms. As a protective response to stress, mitochondrial components enriched in SARM1 were isolated from the mitochondrial network through an increased fission process and were degraded in an autophagy-dependent manner. Importantly, rapamycin (RAPA) administration eliminated mitochondrial accumulated SARM1 and inhibited axon loss. Thus, mitochondrial localization of SARM1 may be complement to the coordinated activity of NMNAT2 and SARM1, and may be part of the self-limiting molecular mechanisms of programmed axon death. In the early latent period, the mitochondrial localization of SARM1 will help it to be isolated by the mitochondrial network and to be degraded through mitophagy to maintain local axon homeostasis. When the mitochondrial quality control mechanisms are broken down, SARM1 will cause irreversible damage for axon death.

scholarly journals Protein Quality Control at the Mitochondrial Surface

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabian den Brave ◽  
Arushi Gupta ◽  
Thomas Becker
Keyword(s):  
Quality Control ◽  
Outer Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Outer Membrane Proteins ◽  
Tom Complex ◽  
Cellular Environment ◽  
Mitochondrial Functions ◽  
Precursor Proteins

Mitochondria contain two membranes, the outer and inner membrane. The outer membrane fulfills crucial functions for the communication of mitochondria with the cellular environment like exchange of lipids via organelle contact sites, the transport of metabolites and the formation of a signaling platform in apoptosis and innate immunity. The translocase of the outer membrane (TOM complex) forms the entry gate for the vast majority of precursor proteins that are produced on cytosolic ribosomes. Surveillance of the functionality of outer membrane proteins is critical for mitochondrial functions and biogenesis. Quality control mechanisms remove defective and mistargeted proteins from the outer membrane as well as precursor proteins that clog the TOM complex. Selective degradation of single proteins is also an important mode to regulate mitochondrial dynamics and initiation of mitophagy pathways. Whereas inner mitochondrial compartments are equipped with specific proteases, the ubiquitin-proteasome system is a central player in protein surveillance on the mitochondrial surface. In this review, we summarize our current knowledge about the molecular mechanisms that govern quality control of proteins at the outer mitochondrial membrane.

scholarly journals PINK1: A Bridge between Mitochondria and Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 371
Author(s):  
Filipa Barroso Gonçalves ◽  
Vanessa Alexandra Morais
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
High Energy ◽  
Common Denominator ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Homeostasis ◽  
Cellular Environment ◽  
Familial Form ◽  
Mitochondrial Functions

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.

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