Life in lights:tracking mitochondrial delivery to lysosomes in vivo

The past decade has seen an intensive and concerted research effort into the molecular regulation of mitophagy, the selective autophagy of mitochondria. Cell-based studies have implicated mitophagy in the pathology of diverse conditions ranging from cancer to neurodegeneration. However, a definitive link between mitophagy and the etiology of human disease remains to be demonstrated. Moreover, we do not know how pervasive mammalian mitophagy is in vivo and fundamental questions remain unanswered. For example, is mitophagy common to all tissues under basal conditions or does it only occur in highly oxidative tissues under stress? This paucity of knowledge is largely due to a lack of experimentally tractable tools that can measure and monitor mitophagy in tissues. Our recent work describes the development of mito-QC, a mouse model to study mitophagy at single cell resolution in vivo

Mitophagy in the aging nervous system

Aging is characterised by the progressive accumulation of cellular dysfunction, stress, and inflammation. A large body of evidence implicates mitochondrial dysfunction as a cause or consequence of age-related diseases including metabolic disorders, neuropathies, various forms of cancer and neurodegenerative diseases. Because neurons have high metabolic demands and cannot divide, they are especially vulnerable to mitochondrial dysfunction which promotes cell dysfunction and cytotoxicity. Mitophagy neutralises mitochondrial dysfunction, providing an adaptive quality control strategy that sustains metabolic homeostasis. Mitophagy has been extensively studied as an inducible stress response in cultured cells and short-lived model organisms. In contrast, our understanding of physiological mitophagy in mammalian aging remains extremely limited, particularly in the nervous system. The recent profiling of mitophagy reporter mice has revealed variegated vistas of steady-state mitochondrial destruction across different tissues. The discovery of patients with congenital autophagy deficiency provokes further intrigue into the mechanisms that underpin neural integrity. These dimensions have considerable implications for targeting mitophagy and other degradative pathways in age-related neurological disease.Peer reviewe

Monitoring autophagy in cancer : From bench to bedside

Autophagy refers to an essential mechanism that evolved to sustain eukaryotic homeostasis and metabolism during instances of nutrient deprivation. During autophagy, intracellular cargo is encapsulated and delivered to the lysosome for elimination. Loss of basal autophagy in vivo negatively impacts cellular proteostasis, metabolism and tissue integrity. Accordingly, many drug development strategies are focused on modulating autophagic capacity in various pathophysiological states, from cancer to neurodegenerative disease. The role of autophagy in cancer is particularly complicated, as either augmenting or attenuating this process can have variable outcomes on cellular survival, proliferation and transformation. This complexity is compounded by the emergence of several selective autophagy pathways, which act to eliminate damaged or superfluous cellular components in a targeted fashion. The advent of sensitive tools to monitor autophagy pathways in vivo holds promise to clarify their importance in cancer pathophysiology. In this review, we provide an overview of autophagy in cancer biology and outline how the development of tools to study autophagy in vivo could enhance our understanding of its function for translational benefit.Peer reviewe

Lipid droplets promote efficient mitophagy

Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.Non peer reviewe

Comment on "mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC"

Peer reviewe

Emerging roles of ATG7 in human health and disease

The cardinal stages of macroautophagy are driven by core autophagy-related (ATG) proteins, whose ablation largely abolishes intracellular turnover. Disrupting ATG genes is paradigmatic of studying autophagy deficiency, yet emerging data suggest that ATG proteins have extensive biological importance beyond autophagic elimination. An important example is ATG7, an essential autophagy effector enzyme that in concert with other ATG proteins, also regulates immunity, cell death and protein secretion, and independently regulates the cell cycle and apoptosis. Recently, a direct association between ATG7 dysfunction and disease was established in patients with biallelic ATG7 variants and childhood-onset neuropathology. Moreover, a prodigious body of evidence supports a role for ATG7 in protecting against complex disease states in model organisms, although how dysfunctional ATG7 contributes to manifestation of these diseases, including cancer, neurodegeneration and infection, in humans remains unclear. Here, we systematically review the biological functions of ATG7, discussing the impact of its impairment on signalling pathways and human pathology. Future studies illuminating the molecular relationship between ATG7 dysfunction and disease will expedite therapies for disorders involving ATG7 deficiency and/or impaired autophagy.Peer reviewe

Mosaic dysfunction of mitophagy in mitochondrial muscle disease

Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.Peer reviewe

CD40 forward signalling is a physiological regulator of early sensory axon growth

Multiple members of the tumour necrosis factor superfamily (TNFSF) regulate the growth and branching of neural processes late in development, when neurons are establishing and refining connections. Here, we present the first evidence that a TNFSF member acts much earlier in development, when axons are growing to their targets. CD40L transiently enhanced axon growth from embryonic mouse DRG neurons cultured at this early stage. Early spinal nerves of embryos lacking the CD40L receptor (Cd40−/− mice) were significantly shorter in vivo than those of Cd40+/+ littermates. CD40L was synthesized in early DRG targets and was co-expressed with CD40 in early DRG neurons. Whereas CD40L enhanced early axon growth independently of neurotrophins, disruption of a CD40L/CD40 autocrine loop impaired early neurotrophin-promoted axon growth. In marked contrast to the widespread regulation of axon and dendrite growth by CD40L reverse signalling later in development, CD40-Fc, which activates reverse signalling, had no effect on early sensory axon growth. These results suggest that CD40 forward signalling is a novel physiological regulator of early axon growth that acts by target-derived and autocrine mechanisms