Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.     

The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment

Thyroid cancer (TC) is the most common type of endocrine malignancy. Tumour formation, progression, and metastasis greatly depend on the efficacy of mitochondria—primarily, the regulation of mitochondria-mediated apoptosis, Ca²⁺ homeostasis, dynamics, energy production, and associated reactive oxygen species generation. Recent studies have successfully confirmed the mitochondrial aetiology of thyroid carcinogenesis. In this review, we focus on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism. We also discuss the repurposing of known drugs and the induction of mitochondria-mediated apoptosis as a new trend in the development of anti-TC therapy.     

The Interplay between Autophagy and NLRP3 Inflammasome in Ischemia/Reperfusion Injury

Ischemia/reperfusion (I/R) injury is characterized by a limited blood supply to organs, followed by the restoration of blood flow and reoxygenation. In addition to ischemia, blood flow recovery can also lead to very harmful injury, especially inflammatory injury. Autophagy refers to the transport of cellular materials to the lysosomes for degradation, leading to the conversion of cellular components and offering energy and macromolecular precursors. It can maintain the balance of synthesis, decomposition and reuse of the intracellular components, and participate in many physiological processes and diseases. Inflammasomes are a kind of protein complex. Under physiological and pathological conditions, as the cellular innate immune signal receptors, inflammasomes sense pathogens to trigger an inflammatory response. TheNLRP3 inflammasome is the most deeply studied inflammasome and is composed of NLRP3, the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18 mediated by caspase-1 and promotes a further inflammatory process. Studies have shown that autophagy and the NLRP3 inflammasome play an important role in the process of I/R injury, but the relevant mechanisms have not been fully explained, especially how the interaction between autophagy and the NLRP3 inflammasome participates in I/R injury, which remains to be further studied. Therefore, we reviewed the recent studies about the interplay between autophagy and the NLRP3 inflammasome in I/R injury and analyzed the mechanisms to provide the theoretical references for further research in the future.     

Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.     

The Mighty Mitochondria Are Unifying Organelles and Metabolic Hubs in Multiple Organs of Obesity,Insulin Resistance,Metabolic Syndrome,and Type 2 Diabetes: An Observational Ultrastructure Study

Mitochondria (Mt) are essential cellular organelles for the production of energy and thermogenesis. Mt also serve a host of functions in addition to energy production, which include cell signaling, metabolism, cell death, and aging. Due to the central role of Mt in metabolism as metabolic hubs, there has been renewed interest in how Mt impact metabolic pathways and multiple pathologies. This review shares multiple observational ultrastructural findings in multiple cells and organs to depict aberrant mitochondrial (aMt) remodeling in pre-clinical rodent models. Further, it is intended to show how remodeling of Mt are associated with obesity, insulin resistance, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM). Specifically, Mt remodeling in hypertensive and insulin-resistant lean models (Ren2 rat models), lean mice with streptozotocin-induced diabetes, obesity models including diet-induced obesity, genetic leptin-deficient ob/ob, and leptin receptor-deficient db/db diabetic mice are examined. Indeed, aMt dysfunction and damage have been implicated in multiple pathogenic diseases. Manipulation of Mt such as the induction of Mt biogenesis coupled with improvement of mitophagy machinery may be helpful to remove leaky damaged aMt in order to prevent the complications associated with the generation of superoxide-derived reactive oxygen species and the subsequent reactive species interactome. A better understanding of Mt remodeling may help to unlock many of the mysteries in obesity, insulin resistance, MetS, T2DM, and the associated complications of diabetic end-organ disease.     

A Reactive Oxygen Species-Responsive Targeted Nanoscavenger to Promote Mitophagy for the Treatment of Alzheimer's Disease

Mitophagy modulators are proposed as potential therapeutic intervention that enhance neuronal health and brain homeostasis in Alzheimer's disease (AD). Nevertheless, the lack of specific mitophagy inducers, low efficacies, and the severe side effects of nonselective autophagy during AD treatment have hindered their application. In this study, the P@NB nanoscavenger is designed with a reactive-oxygen-species-responsive (ROS-responsive) poly(l -lactide-co-glycolide) core and a surface modified with the Beclin1 and angiopoietin-2 peptides. Notably, nicotinamide adenine dinucleotide (NAD⁺) and Beclin1, which act as mitophagy promoters, are quickly released from P@NB in the presence of high ROS levels in lesions to restore mitochondrial homeostasis and induce microglia polarization toward the M2-type, thereby enabling it to phagocytose amyloid-peptide (Aβ). These studies demonstrate that P@NB accelerates Aβ degradation and alleviates excessive inflammatory responses by restoring autophagic flux, which ameliorates cognitive impairment in AD mice. This multitarget strategy induces autophagy/mitophagy through synergy, thereby normalizing mitochondrial dysfunction. Therefore, the developed method provides a promising AD-therapy strategy.