Defective Macroautophagy in Organelle Turnover: From Basic Mechanisms to Human Disease

Schematic representation of selective macroautophagy. Specific cargos, such as dysfunctional organelles or invading microbe, are initially sequestered by the phagophore and engulfed in the forming double-membrane autophagosome. The autophagosome’s outer membrane subsequently fuses with the lysosome releasing the enclosed material in the autolysosome, where the sequestered cargos are degraded by hydrolases.

Editorial

09 September 2022

Editorial: Defective macroautophagy in organelle turnover: From basic mechanisms to human disease

Eloy Bejarano

José Antonio Rodríguez-Navarro

Roberta Filograna

and

Javier Calvo-Garrido

1,233 views

0 citations

Editors

Javier Calvo Garrido

Karolinska Institutet (KI)

Eloy Bejarano Fernandez

Universidad CEU Cardenal Herrera

Roberta Filograna

Karolinska Institutet (KI)

JOSE ANTONIO RODRIGUEZ-NAVARRO

Ramón y Cajal Institute for Health Research

Impact

Circadian clock and regulation of mitochondrial quality control. Figure depicts hypothetical regulation of mitochondrial quality control by the clock. Mitochondria quality control (mitophagy and biogenesis in particular) strongly relays on mitochondrial dynamic (fusion and fission events). Mitochondrial fission generates uneven daughter units, one unit exhibiting increased mitochondrial membrane potential and high probability to fuse, while the other has decreased mitochondrial membrane potential and is degraded by autophagy. The circadian clock regulates mitochondrial fission to allow mitochondrial adaptation to daily metabolic changes. This regulation might also extend to mitochondria quality control. Importantly, one proposed function of sleep (inactive phase) is prevention of oxidative stress build up and degradation of toxic compounds. In light of this, one potential physiological role of sleep during the inactive phase could be to promote mitochondrial quality control as antioxidant response. Created with BioRender.com.

Mini Review

24 August 2022

Mitochondrial autophagy in the sleeping brain

Sofia Mauri

, 3 more and

Elena Ziviani

10,846 views

9 citations

Autophagy and mitophagy are not altered in cells lacking Rnd3 expression. (A) Representative aminoacidic sequences from CRISPR Rnd3 edited cells obtained by single cell cloning (clones #7 and #33) Red letters correspond to wild-type Rnd3 protein and blackletters correspond to the edited sequences. Asterisks represent STOP codons. (B) Rnd3 expression was analyzed by Western blot in different clones. Clone #33, showing no expression of Rnd3, was selected for further analysis (Rnd3 KO). (C) Rnd3 KO cells have no defects in cell growth. Rnd3 WT and KO cell cultures were analyzed as described in Methods. (D) Autophagy is not impaired in Rnd3 KO cells. Autophagy flux was analyzed in the presence or absence of serum. Inhibitors of lysosomal proteolysis (PI) were added to block lysosomal protein degradation. LC3-II levels were analyzed by Western blot (left) as described in Methods and its relative levels are plotted (right panel, n = 5). (E) Analysis of autophagy markers. Cells were treated as in (D) for 6 h and levels of the indicated autophagy markers were analyzed by Western blot (top panels) and relative values were plotted (bottom panels, n = 3). (F) Mitochondria are normally degraded in Rnd3 KO cells. Cells were treated with FCCP to induce mitochondria depolarization and/or with hydroxychloroquine (HCQ) to inhibit mitochondrial degradation. Cells were then stained with MTGreen and analyzed by flow cytometry as described in Methods. Mitophagy flux is plotted (n = 3) as the mean fluorescence intensity. UT, untreated. In all experiments ANOVA analysis showed no differences between Rnd3 WT and Rnd3 KO cells.

Brief Research Report

27 June 2022

Rnd3 Expression is Necessary to Maintain Mitochondrial Homeostasis but Dispensable for Autophagy

Cristina Cueto-Ureña

, 12 more and

Enric Poch

3,270 views

8 citations

Genetic risk factors associated with poor metabolic fitness and defective autophagy in AD. In ApoE4 carriers, the overabundance of ApoE4 in brains threatens the proper lipid transport from astrocytes to neurons, thus leading to decrease autophagic biogenesis in neurons, poor mitochondrial recycling and, as a result, increased production of ROS, promoting pathological conditions that allow amyloid and Tau aggregation. Autophagosomes cointain the elements of the beta secretase, thus, mutations in APP, BACE1 and PS1 increase the production of Aβ, which further interferes with autophagosome formation and aggravates the oxidative stress status of the neurons. Besides, MAPT mutations increase the hyperphosphorylation of Tau and disrupt vesicle trafficking, impeding autophagosome formation and transport. On top of that, peripheral hypercholesterolemia may induces, through different ways, the accumulation of the brain cholesterol metabolite 27-OH, where it mediates a feed-forward loop that downregulates cholesterol synthesis in neurons and astrocytes. This will eventually cause detrimental effects including reduction of synaptic proteins (Psd95, SNAP-25) and Tau hyperphosphorylation, with consequences on autophagosome formation and trafficking, mitochondrial renewal and ROS production.

Review

28 March 2022

Defects of Nutrient Signaling and Autophagy in Neurodegeneration

Jon Ondaro

, 12 more and

Gorka Gereñu

6,212 views

10 citations

Mini Review

14 February 2022

Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging

Anita V. Kumar

, 1 more and

Louis R. Lapierre

Efficient proteostasis is crucial for somatic maintenance, and its decline during aging leads to cellular dysfunction and disease. Selective autophagy is a form of autophagy mediated by receptors that target specific cargoes for degradation and is an essential process to maintain proteostasis. The protein Sequestosome 1 (p62/SQSTM1) is a classical selective autophagy receptor, but it also has roles in the ubiquitin-proteasome system, cellular metabolism, signaling, and apoptosis. p62 is best known for its role in clearing protein aggregates via aggrephagy, but it has recently emerged as a receptor for other forms of selective autophagy such as mitophagy and lipophagy. Notably, p62 has context-dependent impacts on organismal aging and turnover of p62 usually reflects active proteostasis. In this review, we highlight recent advances in understanding the role of p62 in coordinating the ubiquitin-proteasome system and autophagy. We also discuss positive and negative effects of p62 on proteostatic status and their implications on aging and neurodegeneration. Finally, we relate the link between defective p62 and diseases of aging and examine the utility of targeting this multifaceted protein to achieve proteostatic benefits.

39,708 views

175 citations