Dynamic mitophagy trajectories hallmark brain aging.

Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study.

A molecular glue for Prkn/parkin.

Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the , primarily due to mitochondria dysfunction. PRKN (parkin RBR E3 ubiquitin protein ligase) and PINK1 (PTEN induced kinase 1) are linked to early-onset cases of PD and essential for the clearance of damaged mitochondria via selective mitochondrial autophagy (mitophagy). In a recent publication, we detail how a small molecule can activate PRKN mutants that are unable to be phosphorylated, restoring mitophagy in cellular assays.

Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in charcot-marie-tooth type 2 neuropathies.

HSPB1 [heat shock protein family B (small) member 1] and HSPB8 are essential molecular chaperones for neuronal proteostasis, as they prevent protein aggregation. Mutant HSPB1 and HSPB8 primarily harm peripheral neurons, resulting in axonal Charcot-Marie-Tooth neuropathies (CMT2). Macroautophagy/autophagy is a shared mechanism by which HSPB1 and HSPB8 mutations cause neuronal dysfunction.

Blocking autophagosome closure manifests the roles of mammalian Atg8-family proteins in phagophore formation and expansion during nutrient starvation.

Macroautophagy/autophagy, an evolutionarily conserved cellular degradation pathway, involves phagophores that sequester cytoplasmic constituents and mature into autophagosomes for subsequent lysosomal delivery. The gene family, comprising the and subfamilies in mammals, encodes ubiquitin-like proteins that are conjugated to phagophore membranes during autophagosome biogenesis. A central question in the field is how Atg8-family proteins are precisely involved in autophagosome formation, which remains controversial and challenging, at least in part due to the short lifespan of phagophores.

CKAP4 in hepatocellular carcinoma: competitive RETREG1/FAM134B binding, reticulophagy regulation, and cancer progression.

RETREG1/FAM134B is known for its role as a reticulophagy receptor. Our previous study established that RETREG1 is upregulated in hepatocellular carcinoma (HCC) and contributes to disease progression by activating the AKT signaling pathway. However, the specific mechanisms underlying the elevated expression of RETREG1 in HCC remain unclear.

AMPK protects proximal tubular epithelial cells from lysosomal dysfunction and dedifferentiation induced by lipotoxicity.

Renal proximal tubules are a primary site of injury in metabolic diseases. In obese patients and animal models, proximal tubular epithelial cells (PTECs) display dysregulated lipid metabolism, organelle dysfunctions, and oxidative stress that contribute to interstitial inflammation, fibrosis and ultimately end-stage renal failure. Our research group previously pointed out AMP-activated protein kinase (AMPK) decline as a driver of obesity-induced renal disease.

Restoration of lysosomal function attenuates autophagic flux impairment in nucleus pulposus cells and protects against mechanical overloading-induced intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain that incurs large socioeconomic burdens. Growing evidence reveals that macroautophagy/autophagy dysregulation contributes to IVDD, but the exact role of autophagy and its regulatory mechanisms remain largely unknown. Here, we found that mechanical overloading impaired the autophagic flux of nucleus pulposus (NP) cells and .

Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.

MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA.

Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.

Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans.

Rubicon regulates exosome secretion via the non-autophagic pathway.

Exosomes are small extracellular vesicles (EVs), which have the diameter of 50-150 nm and originate from intralumenal vesicles in multivesicular endosomes (MVBs). Exosomes secreted from donor cells are delivered to recipient cells for transferring of exosome cargos, such as proteins, lipids and nucleic acids. The cargo transfer by exosomes has a pivotal role in cell-to-cell communication for many cellular processes; however, the detailed mechanism remains largely elusive.

USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis.

Periodontitis, a prevalent and chronic inflammatory disease, is intricately linked with macroautophagy/autophagy, which has a dual role in maintaining periodontal homeostasis. Despite its importance, the precise interplay between autophagy and periodontitis pathogenesis remains to be fully elucidated. In this study, our investigation revealed that the ubiquitination of RAB7A, mediated by reduced levels of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4), disrupts normal lysosomal trafficking and autophagosome-lysosome fusion, thereby contributing significantly to periodontitis progression.

Autophagy modulates male fertility in arabidopsis.

Macroautophagy/autophagy is a highly conserved catabolic process in eukaryotes and plays pivotal roles in regulating male fertility and sexual reproduction. In metazoans, mutations in core ATG (autophagy related) proteins frequently result in severe defects in sperm formation and maturation, resulting in male sterility. In contrast, autophagy has traditionally been considered dispensable for reproduction in , as most mutants can complete fertilization and produce viable progeny without apparent reproductive defects.

The lipid, PDIM, inhibits the NADPH oxidase and autophagy.

(Mtb), the etiological agent of tuberculosis (TB), remains a significant global health challenge. Mtb is transmitted by respiratory aerosols and infects a variety of myeloid populations. Our recent study shows that the Mtb virulence lipid phthiocerol dimycocerosate (PDIM) promotes the intracellular survival of Mtb in macrophages by inhibiting NADPH oxidase, thereby impairing LC3-associated phagocytosis, and in vivo PDIM also antagonizes canonical macroautophagy/autophagy.

Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death.

Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death.

Autophagy-dependent hepatocyte secretion of DBI/ACBP induced by glucocorticoids determines the pathogenesis of cushing syndrome.

DBI/ACBP is a phylogenetically ancient hormone that stimulates appetite and lipo-anabolism. In response to starvation, DBI/ACBP is secreted through a noncanonical, macroautophagy/autophagy-dependent pathway. The physiological hunger reflex involves starvation-induced secretion of DBI/ACBP from multiple cell types.

Janus-like behavior of intrinsically disordered regions in reticulophagy.

Intrinsically disordered regions (IDRs) are crucial to homeostatic and organellar remodeling pathways. In reticulophagy/ER-phagy, long cytosolic IDR-containing receptors (e.g.

Autophagy as a way to remove DNA lesions.

Type I topoisomerases (TOP1) are critical to remove the topological stress when DNA double strands are unwound. The TOP1 cleavage complexes (TOP1cc) are normally transient, and the stabilization of TOP1cc by its inhibitors, such as camptothecin (CPT), may lead to DNA damage and become cytotoxic. The proteasome pathway degrades trapped TOP1, which is necessary for the repair machinery to gain access to the DNA; however, this process is mainly described when the CPT concentration is high, at levels which are clinically unachievable.

Upregulation of ISG15 induced by MAPT/tau accumulation represses autophagic flux by inhibiting HDAC6 activity: a vicious cycle in alzheimer disease.

Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models and .

acylation of PNPLA2/ATGL: a necessity for triacylglycerol lipolysis and lipophagy in hepatocytes.

The intricate balance between lipolysis and lipophagy in cellular lipid homeostasis has fascinated researchers for years. A growing body of evidence highlights the critical roles of PNPLA2/ATGL (patatin like phospholipase domain containing 2) in both lipolysis and lipophagy. Here, we discuss our recent study, which revealed that PNPLA2 must be S-acylated on Cys15 for its robust catalytic activity.

Impaired chaperone-mediated autophagy leads to abnormal SORT1 (sortilin 1) turnover and CES1-dependent triglyceride hydrolysis.

SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels.

RNF144A inhibits autophagy by targeting BECN1 for degradation during infection.

is widely used in the laboratory as an infection model for the research on pathogenesis and host defense against gram-positive intracellular bacteria. Macroautophagy (called simply "autophagy" hereafter), is important in the host defense against pathogens, such as bacteria, viruses, and parasites. BECN1 plays a pivotal role in the initiation of autophagy and accumulating evidence indicates that post-translational modifications of BECN1 provide multiple strategies for autophagy regulation.

ER quality control through reticulophagy and protein secretion.

The endoplasmic reticulum (ER) is the site of multiple cellular events and maintaining its quality control is thus crucial for cell homeostasis. Through a morphology-based gain-of-function screen, we identified the cytosolic protein FKBPL as a regulator of reticulophagy. With multiple protein-binding domains, FKBPL binds to the ER-resident CKAP4, acting as a bridge that connects the ER to the phagophore and facilitating the delivery of ER contents for lysosomal degradation.

UBAC2 serves as a reticulophagy receptor to suppress inflammatory responses.

Reticulophagy selectively degrades fragments of the endoplasmic reticulum (ER) through macroautophagy/autophagy to maintain ER homeostasis. The deficiency of reticulophagy results in the unfolded protein response (UPR), which is a crucial clue to the pathogenesis of inflammatory diseases. However, the detailed mechanism underlying the cross-regulation between reticulophagy and inflammatory diseases remains largely unclear.

A PRKN-independent mechanism regulating cardiac mitochondrial quality control.

PRKN-dependent mitophagy plays a crucial role in maintaining mitochondrial health. Yet, PRKN-deficient mice do not exhibit mitochondrial and cardiac phenotypes at baseline, suggesting the existence of other mitochondrial ubiquitin (Ub) ligases. Here, we discuss our recent work identifying RNF7/RBX2 as a novel mitochondrial Ub ligase.