Abstract

During homeostasis, crowded cells with the lowest energy levels are eliminated by extrusion via Piezo1 signalling to maintain constant cell numbers. However, crowding-induced extrusion does not necessarily remove damaged or otherwise unfit cells. Here, we show that glucose or glutamine starvation triggers a rapid, regulated wave of extrusion, called starvation-induced cell extrusion (STICE), that selectively eliminates cells bearing DNA damage markers via a p53-dependent, Piezo1-independent pathway, improving monolayer fitness. Unlike non-extruding cells, which recycle contents through autophagy and lysosomal digestion, p53-activated cells instead use LC3 to drive lysosomal exocytosis, promoting extrusion signalling. By eliminating defective and transformed cells, STICE confers resistance to damage and apoptotic stimuli in the remaining monolayer. STICE thus acts as a tissue-level analogue of autophagy: rather than improving individual cells by digesting and recycling damaged components, it improves tissue fitness by eliminating substandard cells.

Abstract

Aging is an inevitable and progressive physiological process marked by a decline in cellular function, accumulation of somatic mutations, decreased ability to maintain homeostasis, and increased tissue and organ dysfunction. These changes contribute to the onset and progression of various age-related diseases. Accumulation of reactive oxygen species (ROS) has been identified as a key mediator of the aging process. Mitochondria, the primary producers of ROS, accumulate defects with aging, leading to increased mitochondrial oxidative stress. These defective mitochondria are both a source and a target of oxidative stress, creating a vicious cycle that accelerates aging and the progression of age-related diseases. Consequently, targeting mitochondria represents a promising therapeutic approach to prevent aging-related physiological dysfunction. MitoQ, a mitochondria-targeted antioxidant, has been extensively studied due to its ability to effectively scavenge mitochondria-derived ROS, owing to its lipophilic cation properties. This review explores the effects of MitoQ on aging-associated physiological dysfunction, specifically exploring its impact on cardiovascular, neuronal, and skeletal muscle functions. By addressing the central role of mitochondrial oxidative stress, we propose that MitoQ represents a promising strategy to counteract aging-associated physiological dysfunction.

ABSTRACT

The human gut hosts approximately 38 trillion bacteria, representing 400 to 500 species. Gut bacteria are in constant communication with the central nervous system (CNS) via the enteric nervous system (ENS), the peripheral nervous system (PNS), the autonomic nervous system (ANS), the immune system, the enteroendocrine system (EES), and the vagus nerve (VN). Short-chain fatty acids (SCFAs), especially butyrate, strengthen the blood-brain barrier (BBB) and modulate inflammatory signaling, thereby affecting brain function and cognitive performance. Acetate enhances the synthesis of lipid-rich myelin that protects neurons. Signaling molecules that cross the gut wall may optimize synaptic signaling in the frontal cortex. Bacterial metabolites that stimulate inflammatory responses activate the hypothalamic-pituitary-adrenal (HPA) axis, thereby increasing glucocorticoid production. This may reduce activity in the prefrontal cortex and suppress higher-order thinking and decision-making. We discuss how signaling molecules produced by gut bacteria influence the limbic system (thalamus, amygdala, hypothalamus, and hippocampus), primarily involved in emotions, memory, and motivation. The HPA axis and the gut microbiota–oligodendrocyte axis (GMOA) are discussed in more detail. We ask whether interactions between signaling molecules produced by gut bacteria and the limbic system can affect human intelligence, cognition, consciousness, and decision-making, coordinated by the cerebrum (cerebral cortex), prefrontal cortex, and parietal lobe.

Editor’s summary

Regulation of lipid metabolism in mitochondria of adipocytes requires integration of information about time of day from the circadian clock, environmental temperature, and nutrient availability. Karavaeva et al. found an important role for the transporter protein SLC25A34 in such control of lipid metabolism and thermogenesis in brown adipocytes from mice and humans (see the Perspective by van der Laan). Inputs from the circadian clock, cold temperatures, and diet all regulated the expression of SLC25A34, allowing control of lipogenesis and mitochondrial biogenesis, lipid oxidation, and thermogenesis. Such regulation may offer insights into inflammation associated with obesity and metabolic diseases. —L. Bryan Ray

Structured Abstract

INTRODUCTION

Brown and beige thermogenic adipocytes (fat cells) have uniquely high energy expenditure capacity. This activity is critical for defending body temperature in small mammals and is linked to cardiometabolic health in humans. Energy expenditure from thermogenic fat cycles daily on a rhythm set by the circadian clock, rising after waking and dropping during sleep. At any point, however, this activity can be suddenly induced by exposure to cold temperature or by ingestion of a calorie-dense, high-fat meal. How thermogenic fat can seamlessly achieve both rhythmic continuity and acute responsiveness is a fundamental question of energy homeostasis that has remained unknown.

RATIONALE

We set out to understand how diverse cues from the body’s clock, environmental temperature, and diet are molecularly integrated in adipocytes to facilitate both anticipatory and adaptive regulation. By combining unbiased analysis of DNA-binding patterns, gene expression, and protein levels in thermogenic fat from mice that were subject to different circadian, environmental, and dietary perturbations, we identified the orphan mitochondrial metabolite transporter SLC25A34 as the convergence point of all three physiological paradigms.

RESULTS

Similar to fat’s thermogenic activity, the expression of Slc25a34 mRNA exhibited a daily rhythm, which was mediated by the nuclear receptors REV-ERBα and REV-ERBβ. REV-ERBs are transcriptional repressors in the circadian clock that recruit histone deacetylase 3 to the Slc25a34 promoter during sleep to shut off transcription. When animals wake and REV-ERB circadian repression is lifted, the peroxisome proliferator–activated receptors α and γ (PPARα and PPARγ) are able to bind the Slc25a34 promoter and restore expression. However, at any time, when animals are suddenly confronted with an unanticipated need for adipocyte energy expenditure such as exposure to cold temperatures or eating a lipid-rich meal, REV-ERB repression is rapidly overridden and PPARs are activated by lipolytic signals to boost SLC25A34 levels. When the energy demand is met, the REV-ERB–mediated rhythmicity of Slc25a34 is reestablished.

Our biochemical and metabolic data support a functional model in which SLC25A34 transports oxaloacetate into mitochondria. In doing so, SLC25A34 helps to maintain high tricarboxylic acid (TCA) cycle activity, which is required for powering energy expenditure in thermogenic adipocytes. The need for SLC25A34 during times of high energetic demand arises because thermogenic adipocytes not only oxidize fatty acids in the mitochondria but also simultaneously synthesize lipids in the cytosol, a process collectively known as lipid cycling. Lipid synthesis requires continuous production of acetyl–coenzyme A (acetyl-CoA) in the cytosol, and the two major pathways responsible for this acetyl-CoA pool also generate oxaloacetate as a by-product, which then needs to be transported back into the mitochondria. Increased cytosolic acetyl-CoA additionally promotes the transcription of genes linked to mitochondrial respiration. Thus, SLC25A34 supports both sides of this self-reinforcing cycle in which lipids are continually broken down and resynthesized.

CONCLUSION

These findings identify SLC25A34 as a molecular node that integrates circadian, temperature, and dietary cues and reveal how thermogenic fat activity can sustain a daily rhythm while remaining acutely responsive to sudden energy demands. This mechanism may offer a new entry point for therapeutically enhancing energy expenditure in metabolic disease.

Abstract

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator–activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl–coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.

Highlights

• • Neuroenergetic flexibility frames brain energy adaptation in aging.
• • Metabolic switching is a component of broader neuroenergetic adaptation.
• • Diet-induced switching alters brain energy metabolism beyond glucose.
• • Mitochondrial plasticity supports adaptation to metabolic stress.
• • A systems framework links metabolic adaptation to brain aging.

Abstract

The aging brain undergoes progressive alterations in energy metabolism that may reduce its capacity to match energy supply with changing functional demands. Declining glucose metabolism, mitochondrial dysfunction, and altered neuron–glia and neurovascular interactions may contribute to this vulnerability, but these changes do not necessarily indicate complete loss of metabolic capacity. Neuroenergetic flexibility refers to the capacity to coordinate changes in substrate utilization with energetic demand while maintaining cellular and functional homeostasis. This review synthesizes evidence from cellular, animal, imaging, and clinical studies to examine the mechanisms underlying this capacity, how it changes with aging, and whether diet-induced metabolic switching can enhance it. Particular attention is given to the distinction between metabolic switching, defined as a change in the relative contribution of available substrates, and neuroenergetic flexibility, which requires coordinated adaptation across substrate delivery, cellular metabolism, mitochondrial processing, neurovascular support, and functional demand. Evidence indicates that ketogenic diets, intermittent fasting, and caloric restriction can alter substrate availability and utilization and can engage mitochondrial, cellular stress-response, and nutrient-sensing pathways. However, the strength of evidence differs across biological levels: changes in alternative-substrate utilization are more consistently demonstrated than coordinated improvements in mitochondrial, vascular, cellular, and functional outcomes. Thus, increased ketone utilization or other metabolic shifts should not, by themselves, be interpreted as evidence of restored neuroenergetic flexibility. Instead, the available evidence suggests that aging may preserve individual metabolic capacities while reducing the coordination and reserve required to adapt effectively to changing energetic demands. Dietary interventions therefore provide useful models for testing metabolic adaptability, but their ability to restore integrated neuroenergetic flexibility in aging or neurodegenerative disease remains uncertain and appears to depend on age, metabolic state, disease context, intervention characteristics, and adherence.

Significance

Alois Mader’s mechanistic model of human muscle energy metabolism was developed more than 40 years ago yet has remained inaccessible to most researchers. Here, we present MetaboliSim, an open-source implementation of Mader’s model that lets researchers perform their own simulations of muscle metabolism during exercise. Because the code is publicly available, the community can refine and extend the model, for example, by reducing simplifying assumptions or incorporating mechanisms not currently represented, such as recruitment of type I and IIa/x muscle fibers, hormonal regulation, or metabolic disease states.

Abstract

Energy metabolism matches adenosine triphosphate (ATP) resynthesis to hydrolysis even during abrupt transitions such as exercise onset. In 1984, Alois Mader proposed a mechanistic model that captures this regulation through 33 coupled differential equations linking oxidative phosphorylation, glycolysis, and the phosphocreatine shuttle via adenosine diphosphate (ADP), phosphate, and pH feedback. Despite its potential, broader adoption has been limited by closed-source implementations and key publications available only in German. Here, we present MetaboliSim, an open-source software tool that simulates muscle energy metabolism in a virtual human parameterized by four physiological inputs: V̇O2max (oxidative capacity), vLamax (glycolytic capacity), body mass, and active muscle mass. Using MetaboliSim, we test Mader’s equations against 10 experimentally established phenomena of exercise metabolism, including ATP homeostasis under fatigue, transient pH alkalinization, glycogen-dependent lactate thresholds, intensity-dependent fat oxidation, the V̇O2 slow component, and work-rate-dependent exhaustion, without altering any equation or constant within the model. Mader’s model qualitatively reproduces all 10 phenomena, generating similarly shaped response curves; absolute values depend on individual parameterization rather than being universally matched. The characteristic inverted-U of fat oxidation and the exercise intensity-dependent V̇O2 kinetics, for example, both emerge from the same equation system. A Sobol sensitivity analysis (S01) reveals a calibration hierarchy: V̇O2max and body mass drive power predictions; vLamax and buffer capacity drive metabolite predictions. That a compact, 40-year-old equation system accounts for this breadth of metabolic phenomena suggests that a small number of regulatory feedback loops may suffice to explain a wide range of metabolic responses to exercise. MetaboliSim is freely available to enable independent testing, empirical calibration, and refinement.