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Intercellular mitochondria transfer has recently attracted substantial attention, both from a fundamental and therapeutic point of view. At the same time, the topic continues to be met with scepticism. In this Viewpoint, different experts in mitochondrial biology share their personal view on the topic.

Navdeep Chandel highlights a study published in 1996 that — by showing that mitochondria can release cytochromecto initiate apoptosis — changed his view of the role of mitochondria in physiology.

A key component of the TCA cycle, a series of reactions that occurs in energy-generating organelles called mitochondria, can dictate the fate of intestinal stem cells.

Mitochondrial electron transport chain activity provides ATP, generates superoxide, regulates apoptosis and provides the biosynthetic building blocks for growing cells. Here Steinert et al. genetically dissect these functions and find that, in the absence of mitochondrial complex III function, acute stimulation results in CD8⁺ T cell exhaustion and that mitochondrial complex III reactive oxygen species are required for establishment of naive and memory populations.

Cellular organelles called mitochondria contain their own DNA and RNA. The molecule fumarate has now been found to trigger the release of these nucleic acids into the cytosol, aberrantly activating inflammation.

Tumour cells with defective mitochondria are found to use glutamine-dependent reductive carboxylation, rather than oxidative metabolism, as the major pathway of citrate and lipid formation.

Does mitochondrial metabolism simply support the bioenergetic and biosynthetic needs of committed immune cells, or does it also control their fate? In this Review, Chandel and colleagues explore variations in mitochondrial metabolism across different immune cells and discuss how mitochondria can act as important signalling organelles to dictate immune cell function.

Hypoxia inhibits the activity of calcium channels in arterial myocytes by unknown mechanisms and contributes to arterial vasodilation. Here, the authors show that myocyte mitochondria are essential for sensing acute hypoxia and generate signals (NADH and H₂O₂) that modulate membrane calcium channels.

Poxviruses replicate in the cytoplasm, making them vulnerable to detection by host nucleic acid sensors. Here the authors show that poxvirus replication induces mitochondrial hyperfusion, resulting in the release of mitochondrial DNA, but that the poxvirus F17 protein counteracts ensuing cGAS activation and increase in glycolysis.

Oxidation of ubiquinol by the mitochondrial electron transfer chain drives tumour growth by maintaining the function of the oxidative Krebs cycle and de novo pyrimidine synthesis.

A COQ6 variant increases susceptibility to pneumococcal infection via non-bone marrow-derived cells without affecting ubiquinone synthesis, challenging traditional views on the metabolic role of COQ6 role and opening new avenues for understanding immunometabolic interactions.

Activation of breathing during hypoxia is abolished in mice lacking mitochondrial complex I in carotid body chemoreceptors, however the specific contribution of mitochondrial complex I to this process is unclear. Here, the authors show that recovery of NADH dehydrogenase activity, but not proton pumping, by transgenic expression of a yeast enzyme rescues cellular and systemic sensitivity to changes in O2 tension.

This study highlights the role of mitochondrial complex I-dependent NAD⁺ regeneration in directing lung epithelial cell fate during postnatal alveolar development by preventing pathological integrated stress response induction.

Using a combination of eye organoids and mouse models the authors identify a bioenergetic independent role of lactate as a cell signaling molecule required during early stages of eye formation in mice.

Here the authors show that epigenetic regulation through the histone acetyltransferase MOF and the acetylation of histone H4 lysine 16 affect essential functions in the mitochondria and primary cilia. This regulation is important to promote epidermal differentiation and hair follicle formation.

Mitochondrial diseases are caused by genetic variants in either nuclear or mitochondrial DNA, and they have no known treatments. A new study by Perry et al. in this issue of Nature Metabolism used a drug screen to identify the widely available antibiotic doxycycline, an inhibitor of mitochondrial translation, as a potential pharmacological treatment for mitochondrial diseases.

How the mitochondrial electron transport chain (ETC) interacts with the NLRP3 inflammasome is somewhat unclear. Here the authors use individual complex inhibitors and new genetic models to show that ETC is critical in providing ATP via the phosphocreatine shuttle to activate the NLRP3 inflammasome.

During aging, the ability of skeletal muscle to repair itself declines, in part due to a decrease in muscle stem cells. Here, the authors report that muscle stem cells that accumulate mitochondrial damage fuse with existing muscle fibers in a manner that depends on the induction of Scinderin.

HOXB13 suppresses a lipogenic transcriptional program in prostate cancer (PCa) through HDAC3 recruitment to enhancers. Loss of HOXB13 leads to lipid accumulation in PCa cells, promoting cell motility in vitro and xenograft tumor metastasis in vivo.

The mechanisms associated with fatty acid synthase (FASN) upregulation during transformation are unclear. Here, the authors report that FASN promotes anaplerotic shift of the Krebs cycle in cancer cells expressing various oncogenes, and that its inhibition before transformation prevents tumour development and invasion.

Using a model of time-restricted feeding in mice, Levine et al. show that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.

Mitochondrial metabolites contribute to more than biosynthesis, and it is clear that they influence multiple cellular functions in a variety of ways. Here, Martínez-Reyes and Chandel review key metabolites and describe their effects on processes involved in physiology and disease including chromatin dynamics, immunity, and hypoxia.

Endothelial cells (ECs) require glycolysis during angiogenesis; however, the function of the mitochondrial respiratory chain during this process is unclear. Here the authors show that mitochondrial respiration in ECs is required for angiogenesis as the biosynthetic role of mitochondria is needed for EC proliferation.

HRD1 is an E3 ligase known to play a role in targeting degradation of misfolded proteins in the ER. Here the authors show that HRD1 interacts with metabolic enzymes and its liver specific deficiency results in lower body weight, blood glucose and plasma lipids during high fat diet in mice.

Microglia rely on mitochondrial respiration to respond to demyelinating injury. However, mitochondrial respiration is not required to support microglial proliferation.

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.

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.

A positive-selection CRISPR screen with the pro-oxidant paraquat (PQ) uncovers three genes mediating PQ-induced cell death: POR is the source of PQ-mediated reactive oxygen species (ROS) generation, and ATP7A and SLC45A4 promote oxidant-dependent cell death.

Cells closely monitor mitochondrial status. Liu and colleagues show that the kinase Jnk2 regulates mitophagy by inhibiting smARF. Loss of Jnk2 results in defective mitophagy and enhanced ROS generation during hypoxia, which leads to enhanced inflammasome activation.

Markov, Ren, Senkow and colleagues report that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterized patients who recovered, whereas responses against nonstructural proteins and activation of NF-κB were associated with poor outcomes.

We are approaching the 100th anniversary of Otto Warburg’s first description of the metabolic phenotype bearing his name—a propensity for tumours to metabolize glucose anaerobically rather than aerobically, even when oxygen is available. Generations of scientists have studied the Warburg effect, yet misconceptions persist about its causes and relationship to oxidative metabolism in the mitochondria. Here, we review the definition of the Warburg effect and discuss its place within a modern understanding of cancer biology.

Recent studies indicate that macrophages utilize NAD⁺-biosynthetic pathways to control inflammation and cell survival during the immune response and aging.

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.

Passegué and colleagues discuss recent advances in our understanding of the metabolic control of stem cell function, and how stem cell metabolism relates to homeostasis and ageing.

The authors found that, across tissues and in multiple datasets, aging is accompanied by a length-associated transcriptome imbalance. In most cases, a decrease in the relative abundance of long transcripts was observed and could be reversed by interventions targeting aging.

Analysis of bronchoalveolar lavage fluid samples from patients with SARS-CoV-2-induced respiratory failure suggests that SARS-CoV-2 infects alveolar macrophages to cause release of T cell chemoattractants, thereby inducing local inflammatory cytokine release and further T cell activation, ultimately resulting in a positive feedback loop that drives alveolar inflammation.

Franzoso and colleagues show that NF-κB protects cells from nutrient-starvation-induced necrosis by upregulating mitochondrial respiration through increased p53-dependent expression of the SCO2 enzyme. Conversely, inhibition of NF-κB results in increased aerobic glycolysis, known as the Warburg effect, thus promoting oncogenic transformation, and affects metabolic adaptation during tumorigenesis in vivo.

A mechanism is suggested that helps tumour cells survive energy stress conditions during early stages of tumorigenesis.

This Perspective discusses the main themes in cancer metabolism research that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing emerging aspects and questions that remain unanswered.

Reactive oxygen species (ROS) comprise a wide variety of oxidant molecules with vastly different properties and biological functions in physiology and in disease. Approaches to characterize oxidants in the in vivo context and identify their specific cellular targets will be required to understand and control the pathophysiological activities of ROS.

Understanding how tumor cells utilize metabolic pathways for proliferation may provide useful strategies for combating cancer. A Perspective discusses recent advances in cancer drug development that target specific aspects of mitochondrial biosynthesis and bioenergetics processes.

The transcriptional response to hypoxia and the role of hypoxia inducible factors have been extensively studied. Yet, hypoxic cells also adapt to hypoxia by modulating protein synthesis, metabolism and nutrient uptake. Understanding these processes could shed light on pathologies associated with hypoxia, including cardiovascular diseases and cancer, and disease mechanisms, such as inflammation and wound repair.