Mitochondrial Stress Response Pathway Research Articles

Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression

Depression, or major depressive disorder, poses a significant burden for both individuals and society, affecting approximately 10.8% of the general population. This psychiatric disorder leads to approximately 800,000 deaths per year. A combination of genetic and environmental factors such as early life stress (ELS) increase the risk for development of depression in humans, and a clear role for the hippocampus in the pathophysiology of depression has been shown. Nevertheless, the underlying mechanisms of depression remain poorly understood, resulting in a lack of effective treatments. To better understand the core mechanisms underlying the development of depression, we used a cross-species design to investigate shared hippocampal pathophysiological mechanisms in mouse ELS and human depression. Mice were subjected to ELS by a maternal separation paradigm, followed by RNA sequencing analysis of the adult hippocampal tissue. This identified persistent transcriptional changes linked to mitochondrial stress response pathways, with oxidative phosphorylation and protein folding emerging as the main mechanisms affected by maternal separation. Remarkably, there was a significant overlap between the pathways involved in mitochondrial stress response we observed and publicly available RNAseq data from hippocampal tissue of depressive patients. This cross-species conservation of changes in gene expression of mitochondria-related genes suggests that mitochondrial stress may play a pivotal role in the development of depression. Our findings highlight the potential significance of the hippocampal mitochondrial stress response as a core mechanism underlying the development of depression. Further experimental investigations are required to expand our understanding of these mechanisms.

The Role of Mitokines in Diabetic Nephropathy.

Diabetic nephropathy (DN) has gradually become one of the main causes of end-stage renal disease (ESRD). However, there is still a lack of effective preventive measures to delay its progression. As the energy factory in the cell, mitochondria play an irreplaceable role in maintaining cell homeostasis. Interestingly, recent studies have shown that in addition to maintaining homeostasis in cells in which mitochondria reside, when mitochondrial perturbations occur in one tissue, distal tissues can also sense and act through mitochondrial stress response pathways through a group of proteins or peptides called "mitokines". Here, we reviewed the mitokines that have been found thus far and summarized their research progress in DN. Finally, we explored the possibility of mitokines as potential therapeutic targets for DN.

Cobalt chloride has beneficial effects across species through a hormetic mechanism.

Severe oxygen and iron deficiencies have evolutionarily conserved detrimental effects, leading to pathologies in mammals and developmental arrest as well as neuromuscular degeneration in the nematode Caenorhabditis elegans. Yet, similar to the beneficial effects of mild hypoxia, non-toxic levels of iron depletion, achieved with the iron chelator bipyridine or through frataxin silencing, extend C. elegans lifespan through hypoxia-like induction of mitophagy. While the positive health outcomes of hypoxia preconditioning are evident, its practical application is rather challenging. Here, we thus test the potential beneficial effects of non-toxic, preconditioning interventions acting on iron instead of oxygen availability. We find that limiting iron availability through the iron competing agent cobalt chloride has evolutionarily conserved dose-dependent beneficial effects: while high doses of cobalt chloride have toxic effects in mammalian cells, iPS-derived neurospheres, and in C. elegans, sub-lethal doses protect against hypoxia- or cobalt chloride-induced death in mammalian cells and extend lifespan and delay age-associated neuromuscular alterations in C. elegans. The beneficial effects of cobalt chloride are accompanied by the activation of protective mitochondrial stress response pathways.

Multifaceted roles of mitochondrial stress responses under ETC dysfunction - repair, destruction and pathogenesis.

Electron transport chain (ETC) dysfunction is a common feature of mitochondrial diseases and induces severe cellular stresses, including mitochondrial membrane potential (Δψm ) reduction, mitochondrial matrix acidification, metabolic derangements and proteostatic stresses. Extensive studies of ETC dysfunction in yeast, Caenorhabditis elegans, cultured cells and mouse models have revealed multiple mitochondrial stress response pathways. Here, we summarise the current understanding of the triggers, sensors, signalling mechanisms and the functional outcomes of mitochondrial stress responses in different species. We highlight Δψm reduction as a major trigger of stress responses in different species, but the responses are species-specific and the outcomes are context-dependent. ETC dysfunction elicits a mitochondrial unfolded protein response (UPRmt ) to repair damaged mitochondria in C. elegans, and activates a global adaptive programme to maintain Δψm in yeast. Yeast and C. elegans responses are remarkably similar at the downstream responses, although they are activated by different signalling mechanisms. UPRmt generally protects ETC-defective worms, but its constitutive activation is toxic for wildtype worms and worms carrying mutant mtDNA. In contrast to lower organisms, ETC dysfunction in mammals mainly activates a mitochondrial integrated stress response (ISRmt ) to reprogramme metabolism and a PINK1-Parkin mitophagy pathway to degrade damaged mitochondria. Accumulating in vivo results suggest that the ATF4 branch of ISRmt exacerbates metabolic derangements to accelerate mitochondrial disease progression. The in vivo roles of mitophagy in mitochondrial diseases are also context-dependent. These results thus reveal the common and unique aspects of mitochondrial stress responses in different species and highlight their multifaceted roles in mitochondrial diseases.

FANCD2 modulates the mitochondrial stress response to prevent common fragile site instability

Common fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability involves transcription- and replication-dependent mechanisms. Here, we uncover a role for the mitochondrial stress response pathway in the regulation of CFS stability in human cells. We show that FANCD2, a master regulator of CFS stability, dampens the activation of the mitochondrial stress response and prevents mitochondrial dysfunction. Genetic or pharmacological activation of mitochondrial stress signaling induces CFS gene expression and concomitant relocalization to CFSs of FANCD2. FANCD2 attenuates CFS gene transcription and promotes CFS gene stability. Mechanistically, we demonstrate that the mitochondrial stress-dependent induction of CFS genes is mediated by ubiquitin-like protein 5 (UBL5), and that a UBL5-FANCD2 dependent axis regulates the mitochondrial UPR in human cells. We propose that FANCD2 coordinates nuclear and mitochondrial activities to prevent genome instability.

Dynamic Proteomics Profiling of <i>Legionella pneumophila</i> Infection Unveils Modulation of the Host Mitochondrial Stress Response Pathway

The human pathogen Legionella pneumophila (L.p.) secretes ~330 bacterial effector proteins into the host cell which interfere with numerous cellular pathways and often regulate host cell proteins through post-translational modifications. However, the cellular targets and functions of most L.p. effectors are not known. In order to obtain a global overview of potential targets of these effectors, we analyzed the host cell proteome, ubiquitinome, and phosphoproteome during L.p. infection. Our analysis reveals dramatic spatiotemporal changes in the host cell proteome that are dependent on the secretion of bacterial effectors. Strikingly, we show that L.p. substantially reshapes the mitochondrial proteome and modulates mitochondrial stress response pathways such as the mitochondrial unfolded protein response (UPRmt). To our knowledge, this is the first evidence of manipulation of the UPRmt by a bacterial pathogen in mammalian cells. In addition, we have identified a previously uncharacterized L.p. effector that is targeted to host cell mitochondria and protects mitochondrial network integrity during mitochondrial stress.

Apoptosis inducing factor deficiency causes retinal photoreceptor degeneration. The protective role of the redox compound methylene blue

Dysfunction in mitochondrial oxidative phosphorylation (OXPHOS) underlies a wide spectrum of human ailments known as mitochondrial diseases. Deficiencies in complex I of the electron transport chain (ETC) contribute to 30–40% of all cases of mitochondrial diseases, and leads to eye disease including optic nerve atrophy and retinal degeneration. The mechanisms responsible for organ damage in mitochondrial defects may include energy deficit, oxidative stress, and an increase in the NADH/NAD+ redox ratio due to decreased NAD+ regeneration. Currently, there is no effective treatment to alleviate human disease induced by complex I defect.Photoreceptor cells have the highest energy demand and dependence on OXPHOS for survival, and the lowest reserve capacity indicating that they are sensitive to OXPHOS defects. We investigated the effect of mitochondrial OXPHOS deficiency on retinal photoreceptors in a model of mitochondrial complex I defect (apoptosis inducing factor, AIF-deficient mice, Harlequin mice), and tested the protective effect of a mitochondrial redox compound (methylene blue, MB) on mitochondrial and photoreceptor integrity. MB prevented the reduction in the retinal thickness and protein markers for photoreceptor outer segments, Muller and ganglion cells, and altered mitochondrial integrity and function induced by AIF deficiency. In rotenone-induced complex I deficient 661 W cells (an immortalized mouse photoreceptor cell line) MB decreased the NADH/NAD+ ratio and oxidative stress without correcting the energy deficit, and improved cell survival. MB deactivated the mitochondrial stress response pathways, the unfolding protein response and mitophagy. In conclusion, preserving mitochondrial structure and function alleviates retinal photoreceptor degeneration in mitochondrial complex I defect.

Microfluidics-enabled phenotyping of a whole population of C. elegans worms over their embryonic and post-embryonic development at single-organism resolution

The organism Caenorhabditis elegans is a performant model system for studying human biological processes and diseases, but until now all phenome data are produced as population-averaged read-outs. Monitoring of individual responses to drug treatments would however be more informative. Here, a new strategy to track different phenotypic traits of individual C. elegans nematodes throughout their full life-cycle—i.e., embryonic and post-embryonic development, until adulthood onset, differently from life-span—is presented. In an automated fashion, single worms were synchronized, isolated, and cultured from egg to adulthood in a microfluidic device, where their identity was preserved during their whole development. Several phenotypes were monitored and quantified for each animal, resulting in high-content phenome data. Specifically, the method was validated by analyzing the response of C. elegans to doxycycline, an antibiotic fairly well-known to prolong the development and activate mitochondrial stress-response pathways in different species. Interestingly, the obtained extensive single-worm phenome not only confirmed the dramatic doxycycline effect on the worm developmental delay, but more importantly revealed subtle yet severe treatment-dependent phenotypes that are representative of minority subgroups and would have otherwise stayed hidden in an averaged dataset. Such heterogeneous response started during the embryonic development, which makes essential having a dedicated chip that allows including this early developmental stage in the drug assay. Our approach would therefore allow elucidating pharmaceutical or therapeutic responses that so far were still being overlooked.

Mitochondrial Toxicity.

Recent decades have seen a rapid increase in reported toxic effects of drugs and pollutants on mitochondria. Researchers have also documented many genetic differences leading to mitochondrial diseases, currently reported to affect ∼1 person in 4,300, creating a large number of potential gene-environment interactions in mitochondrial toxicity. We briefly review this history, and then highlight cutting-edge areas of mitochondrial research including the role of mitochondrial reactive oxygen species in signaling; increased understanding of fundamental biological processes involved in mitochondrial homeostasis (DNA maintenance and mutagenesis, mitochondrial stress response pathways, fusion and fission, autophagy and biogenesis, and exocytosis); systemic effects resulting from mitochondrial stresses in specific cell types; mitochondrial involvement in immune function; the growing evidence of long-term effects of mitochondrial toxicity; mitochondrial-epigenetic cross-talk; and newer approaches to test chemicals for mitochondrial toxicity. We also discuss the potential importance of hormetic effects of mitochondrial stressors. Finally, we comment on future areas of research we consider critical for mitochondrial toxicology, including increased integration of clinical, experimental laboratory, and epidemiological (human and wildlife) studies; improved understanding of biomarkers in the human population; and incorporation of other factors that affect mitochondria, such as diet, exercise, age, and nonchemical stressors.

A multimethod computational simulation approach for investigating mitochondrial dynamics and dysfunction in degenerative aging.

SummaryResearch in biogerontology has largely focused on the complex relationship between mitochondrial dysfunction and biological aging. In particular, the mitochondrial free radical theory of aging (MFRTA) has been well accepted. However, this theory has been challenged by recent studies showing minimal increases in reactive oxygen species (ROS) as not entirely deleterious in nature, and even beneficial under the appropriate cellular circumstances. To assess these significant and nonintuitive observations in the context of a functional system, we have taken an in silico approach to expand the focus of the MFRTA by including other key mitochondrial stress response pathways, as they have been observed in the nematode Caenorhabditis elegans. These include the mitochondrial unfolded protein response (UPR mt), mitochondrial biogenesis and autophagy dynamics, the relevant DAF‐16 and SKN‐1 axes, and NAD +‐dependent deacetylase activities. To integrate these pathways, we have developed a multilevel hybrid‐modeling paradigm, containing agent‐based elements among stochastic system‐dynamics environments of logically derived ordinary differential equations, to simulate aging mitochondrial phenotypes within a population of energetically demanding cells. The simulation experiments resulted in accurate predictions of physiological parameters over time that accompany normal aging, such as the declines in both NAD + and ATP and an increase in ROS. Additionally, the in silico system was virtually perturbed using a variety of pharmacological (e.g., rapamycin, pterostilbene, paraquat) and genetic (e.g., skn‐1, daf‐16, sod‐2) schemes to quantitate the temporal alterations of specific mechanistic targets, supporting insights into molecular determinants of aging as well as cytoprotective agents that may improve neurological or muscular healthspan.

TSPO: functions and applications of a mitochondrial stress response pathway.

The mitochondrial outer membrane protein TSPO (translocator protein) lies in a privileged position at the interface between mitochondrion and cytosol. Since the initially discovery, nearly forty years ago, it has generated major interest among various disciplines of modern experimental and applied biomedicine. The focused meeting we have organized aimed at summarizing the state of the art knowledge on TSPO and the discipline-based segregated concepts that have made this an exciting and active field of science. The scientists who have generously contributed the event have agreed to generate a special issue here published--stemmed from the discussion of the vent. This consists in a series of contributions via which the know-how is shared aiming to inspire current and future endeavours to validate and accelerate the impact of TSPO science in human pathophysiology and clinical applications.

The Cell-Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity

The life span of C. elegans can be increased via reduced function of the mitochondria; however, the extent to which mitochondrial alteration in a single, distinct tissue may influence aging in the whole organism remains unknown. We addressed this question by asking whether manipulations to ETC function can modulate aging in a cell-non-autonomous fashion. We report that the alteration of mitochondrial function in key tissues is essential for establishing and maintaining a prolongevity cue. We find that regulators of mitochondrial stress responses are essential and specific genetic requirements for the electron transport chain (ETC) longevity pathway. Strikingly, we find that mitochondrial perturbation in one tissue is perceived and acted upon by the mitochondrial stress response pathway in a distal tissue. These results suggest that mitochondria may establish and perpetuate the rate of aging for the whole organism independent of cell-autonomous functions.