Cells

Editorial

Jump to: Research, Review

3 pages, 220 KiB

Open AccessEditorial

Autophagy Meets Aging: An Overview

by Anna Picca, Emanuele Marzetti and Christiaan Leeuwenburgh

Cells 2023, 12(3), 489; https://doi.org/10.3390/cells12030489 - 2 Feb 2023

Cited by 2 | Viewed by 1961

Abstract

Aging is characterized by biological disarrangements that increase vulnerability to stressors, the development of chronic diseases (e [...] Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

Research

Jump to: Editorial, Review

19 pages, 7094 KiB

Open AccessArticle

Autophagy and Lysosomal Functionality in CMT2B Fibroblasts Carrying the RAB7^K126R Mutation

by Roberta Romano, Victoria Stefania Del Fiore, Paola Saveri, Ilaria Elena Palamà, Chiara Pisciotta, Davide Pareyson, Cecilia Bucci and Flora Guerra

Cells 2022, 11(3), 496; https://doi.org/10.3390/cells11030496 - 31 Jan 2022

Cited by 10 | Viewed by 3480

Abstract

Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by five mutations in the RAB7A gene. Autophagy and late endocytic trafficking were already characterized in CMT2B. Indeed, impairment of autophagy and an increase in lysosomal degradative activity were found in [...] Read more.

Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by five mutations in the RAB7A gene. Autophagy and late endocytic trafficking were already characterized in CMT2B. Indeed, impairment of autophagy and an increase in lysosomal degradative activity were found in cells expressing the mutant proteins. Recently, we described a novel RAB7 mutation associated with predominantly motor CMT2 and impaired EGFR trafficking. With the aim to analyze the autophagy process and lysosomal activity in CMT2B fibroblasts carrying the p.K126R RAB7 novel mutation and to investigate further the causes of the different phenotype, we have performed Western blot, immunofluorescence and cytometric analyses monitoring autophagic markers and endocytic proteins. Moreover, we investigated lipophagy by analyzing accumulation of lipid droplets and their co-localization with endolysosomal degradative compartments. We found that cells expressing the RAB7^K126R mutant protein were characterized by impairment of autophagy and lipophagy processes and by a moderate increase in lysosomal activity compared to the previously studied cells carrying the RAB7^V162M mutation. Thus, we concluded that EGFR trafficking alterations and a moderate increase in lysosomal activity with concomitant impairment of autophagy could induce the specific predominantly motor phenotype observed in K126R patients. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

16 pages, 4326 KiB

Open AccessFeature PaperArticle

Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers

by Joseph Flores-Toro, Sung-Kook Chun, Jun-Kyu Shin, Joan Campbell, Melissa Lichtenberger, William Chapman, Ivan Zendejas, Kevin Behrns, Christiaan Leeuwenburgh and Jae-Sung Kim

Cells 2021, 10(8), 1863; https://doi.org/10.3390/cells10081863 - 23 Jul 2021

Cited by 9 | Viewed by 2675

Abstract

Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is [...] Read more.

Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than that in young counterparts. However, reperfusion substantially decreased CAST in aged human and mouse livers. In hepatocytes, reperfusion rapidly depleted aged cells of CAST, cleaved autophagy-related protein 5 (ATG5), and induced defective autophagy and MPT onset, all of which were blocked by CAST overexpression. Furthermore, mitochondrial morphology was shifted toward an elongated shape with CAST overexpression. In conclusion, CAST in aged livers is intrinsically short-lived and lost after short I/R. CAST depletion contributes to age-dependent liver injury after I/R. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

16 pages, 10219 KiB

Open AccessArticle

Impaired F₁F_o-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging

by Verena Warnsmann, Lisa-Marie Marschall and Heinz D. Osiewacz

Cells 2021, 10(4), 757; https://doi.org/10.3390/cells10040757 - 30 Mar 2021

Cited by 14 | Viewed by 2401

Abstract

Mitochondrial F₁F_o-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F₁F_o-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, [...] Read more.

Mitochondrial F₁F_o-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F₁F_o-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F₁F_o-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

16 pages, 2959 KiB

Open AccessArticle

Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults

by Anna Picca, Sunil K. Saini, Robert T. Mankowski, George Kamenov, Stephen D. Anton, Todd M. Manini, Thomas W. Buford, Stephanie E. Wohlgemuth, Rui Xiao, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Roberto Bernabei, David A. Hood, Emanuele Marzetti and Christiaan Leeuwenburgh

Cells 2020, 9(12), 2579; https://doi.org/10.3390/cells9122579 - 2 Dec 2020

Cited by 20 | Viewed by 3987

Abstract

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial–iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from [...] Read more.

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial–iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA⁴⁹⁷⁷) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope (⁵⁶Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA⁴⁹⁷⁷ relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

13 pages, 1083 KiB

Open AccessReview

The AMPK/p27^Kip1 Pathway as a Novel Target to Promote Autophagy and Resilience in Aged Cells

by Lauren K. McKay and James P. White

Cells 2021, 10(6), 1430; https://doi.org/10.3390/cells10061430 - 8 Jun 2021

Cited by 21 | Viewed by 5089

Abstract

Once believed to solely function as a cyclin-dependent kinase inhibitor, p27^Kip1 is now emerging as a critical mediator of autophagy, cytoskeletal dynamics, cell migration and apoptosis. During periods of metabolic stress, the subcellular location of p27^Kip1 largely dictates its function. Cytoplasmic [...] Read more.

Once believed to solely function as a cyclin-dependent kinase inhibitor, p27^Kip1 is now emerging as a critical mediator of autophagy, cytoskeletal dynamics, cell migration and apoptosis. During periods of metabolic stress, the subcellular location of p27^Kip1 largely dictates its function. Cytoplasmic p27^Kip1 has been found to be promote cellular resilience through autophagy and anti-apoptotic mechanisms. Nuclear p27^Kip1, however, inhibits cell cycle progression and makes the cell susceptible to quiescence, apoptosis, and/or senescence. Cellular location of p27^Kip1 is regulated, in part, by phosphorylation by various kinases, including Akt and AMPK. Aging promotes nuclear localization of p27^Kip1 and a predisposition to senescence or apoptosis. Here, we will review the role of p27^Kip1 in healthy and aging cells with a particular emphasis on the interplay between autophagy and apoptosis. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

21 pages, 1294 KiB

Open AccessReview

Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle

by Matthew Triolo and David A. Hood

Cells 2021, 10(5), 1054; https://doi.org/10.3390/cells10051054 - 29 Apr 2021

Cited by 28 | Viewed by 5450

Abstract

Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging [...] Read more.

Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

26 pages, 1085 KiB

Open AccessReview

Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans

by Georgios Konstantinidis and Nektarios Tavernarakis

Cells 2021, 10(3), 694; https://doi.org/10.3390/cells10030694 - 21 Mar 2021

Cited by 12 | Viewed by 6160

Abstract

Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic [...] Read more.

Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane organelle referred to as the autophagosome with subsequent degradation of its contents upon delivery to lysosomes. Autophagy plays critical roles in development, maintenance and survival of distinct cell populations including neurons. Consequently, age-dependent decline in autophagy predisposes animals for age-related diseases including neurodegeneration and compromises healthspan and longevity. In this review, we summarize recent advances in our understanding of the role of neuronal autophagy in ageing, focusing on studies in the nematode Caenorhabditis elegans. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

30 pages, 2033 KiB

Open AccessReview

Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting

by Azin Amin, Nirma D. Perera, Philip M. Beart, Bradley J. Turner and Fazel Shabanpoor

Cells 2020, 9(11), 2413; https://doi.org/10.3390/cells9112413 - 4 Nov 2020

Cited by 54 | Viewed by 7938

Abstract

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is [...] Read more.

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular “clearance” system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS. Full article

(This article belongs to the Special Issue Autophagy Meets Aging)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Autophagy Meets Aging

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (9 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI