Explore the vast range of titles available.

Key Points Mitochondria contribute to the generation of ATP through oxidative phosphorylation, but they also participate in biosynthetic, metabolic and signalling functions in the cell. Some of the signalling functions are mediated by reactive oxygen species (ROS) that are generated by the electron transport chain. Alterations in mitochondrial ROS generation have been linked to a wide range of tumour cell types. Mitochondria generate ROS when electrons residing on flavin groups, iron–sulphur centres or other electron transport 'way-stations' are diverted to O 2 , generating superoxide. Diverse 'antioxidant enzymes' scavenge ROS and/or reverse the effects of ROS on proteins, lipids and DNA, thereby limiting the scope of oxidative damage or redox signalling. Mitochondrial ROS generation can be important in cancer because it activates cellular redox signalling that drives proliferative responses and triggers activation of transcription factors that promote tumorigenesis and survival, such as hypoxia-inducible factors (HIFs). Hypoxia triggers a paradoxical increase in the release of ROS from complex III to the mitochondrial intermembrane space, facilitating signalling, cell survival and proliferation. Mitochondrial DNA can be damaged by ROS, and mutant mitochondrial proteins can augment ROS generation, creating a vicious cycle that contributes to cancer initiation or progression. Mitochondrial DNA mutations have been linked to a wide range of cancer types. In some cases, mitochondrial DNA mutations regulate the tumorigenic phenotype through their effect on ROS generation. Mitochondrial ROS can contribute to genomic instability, and can contribute to the activation of mitochondria-dependent cell death pathways. However, a fuller understanding of the how altered mitochondrial ROS generation contributes to cancer progression is needed. Oncogenes such as KRAS and MYC drive tumorigenesis in part by augmenting mitochondrial ROS generation. As many tumour cells benefit from mitochondria-derived redox signalling, a useful therapeutic approach could revolve around the inhibition of tumour-promoting mitochondrial ROS signalling without interfering with ATP production. Such an approach could limit the ability of cells to activate protective responses, leaving them vulnerable to cytotoxic agents. Reactive oxygen species (ROS) are generated through various mechanisms. Accumulating evidence indicates that these moieties have important roles in promoting tumorigenesis and tumour progression; modulating the redox balance could be a strategy in targeting cancer. Mitochondria cooperate with their host cells by contributing to bioenergetics, metabolism, biosynthesis, and cell death or survival functions. Reactive oxygen species (ROS) generated by mitochondria participate in stress signalling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behaviour. As mitochondria carry out important functions in normal cells, disabling their function is not a feasible therapy for cancer. However, ROS signalling contributes to proliferation and survival in many cancers, so the targeted disruption of mitochondria-to-cell redox communication represents a promising avenue for future therapy.

Adult and fetal haematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron-sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anaemia and prenatal death. RISP-null fetal HSCs displayed impaired respiration resulting in a decreased NAD + /NADH ratio. RISP-null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation associated with increases in 2-hydroxyglutarate (2HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence concomitant with severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence. Two papers by Liu et al. and Ansó et al. study the post-transcriptional regulation of mitochondrial factors in erythropoiesis and the role of RISP-mediated mitochondrial respiration in fetal and adult HSC function via metabolites and epigenetic changes.

Bronchopulmonary dysplasia (BPD) is a disorder that affects newborn infants, particularly those born prematurely. The lungs are acutely affected by BPD, but the underlying mechanisms are not fully understood. Rodent models have provided insight into the pathogenesis of BPD, showing evidence of impaired lung development and vascularization. Reactive oxygen species (ROS) and oxidative stress play a role in the dysfunctional lung growth observed in these models. However, antioxidant therapies have shown limited efficacy in treating BPD. In a recent study, Jing et al investigated the role of oxidant stress, endoplasmic reticulum stress, and DNA damage in a rat model of BPD. They found evidence of oxidative stress and DNA damage in human lung samples from BPD patients, suggesting the activation of cellular senescence. The study also implicated endoplasmic reticulum stress and neutrophil-mediated oxidative damage in the development of senescence in lung cells. While the study provides valuable insights, further research is needed to confirm these findings and determine the relative contributions of different cellular responses in BPD.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease 1 . Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear 2 . Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm 3 , 4 . Dysfunction of mitochondrial complex I in mice is sufficient to cause progressive parkinsonism in which the loss of nigral dopamine release critically contributes to motor dysfunction.

Schumacker discusses study on mitochondrial succinate dehydrogenase in chronic obstructive pulmonary disease (COPD). Chronic obstructive pulmonary disease (COPD) is best known for its limiting effects on expiratory airflow in the lung. However, COPD affects more than just the lung, as patients with this disease also develop systemic disorders that contribute significantly to morbidity and mortality. One of these comorbidities involves skeletal muscle weakness, which can impair ambulation and affect the respiratory muscles, including the diaphragm. Muscle function is characterized by muscle fiber strength, the ability to generate contractile force, and muscle endurance, the ability to sustain a degree of continuous activity without developing fatigue.

Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (H2O2). We show that MAO metabolism of DA does not increase cytosolic H2O2 but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release.Graves et al. demonstrate that as the neurotransmitter dopamine cycles through the cytosol at release sites, it can be metabolized by a mitochondrial enzyme to help generate the energy necessary to sustain synaptic function.

Regulatory T cells (T reg cells), a distinct subset of CD4 + T cells, are necessary for the maintenance of immune self-tolerance and homeostasis 1 , 2 . Recent studies have demonstrated that T reg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4 + effector subsets 3 , 4 . Furthermore, the T reg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration 5 , 6 ; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T reg cells. Here we report that T reg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting T reg cell number. Mice that lack mitochondrial complex III specifically in T reg cells displayed a loss of T cell-suppression capacity without altering T reg cell proliferation and survival. T reg cells deficient in complex III showed decreased expression of genes associated with T reg function, whereas Foxp3 expression remained stable. Loss of complex III in T reg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases 7 . Thus, T reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function. Specific ablation of mitochondrial complex III subunits in T reg cells in mice results in inflammatory disease, altered T reg gene expression and defective T reg function, indicating a key functional role for mitochondrial complex III in T reg cells.

Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo. Reactive oxygen species (ROS) have important roles in health and disease, but are chemically complex and difficult to measure accurately. This consensus statement proposes guidelines and best practices on the nomenclature and assessment of ROS, oxidative reactions and oxidative damage in cells, tissues and in vivo.

The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass - demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.