Mitochondrial energy state controls AMPK-mediated foraging behavior in C. elegans.

Organisms surveil and respond to their environment using behaviors entrained by metabolic cues that reflect food availability. Mitochondria act as metabolic hubs and at the center of mitochondrial energy production is the protonmotive force (PMF), an electrochemical gradient generated by metabolite consumption. The PMF serves as a central integrator of mitochondrial status, but its role in governing metabolic signaling is poorly understood. We used optogenetics to dissipate the PMF in Caenorhabditis elegans tissues to test its role in food-related behaviors. Our data demonstrate that PMF reduction in the intestine is sufficient to initiate locomotor responses to acute food deprivation. This behavioral adaptation requires the cellular energy regulator AMP-activated protein kinase (AMPK) in neurons, not in the intestine, and relies on mitochondrial dynamics and axonal trafficking. Our results highlight a role for intestinal PMF as an internal metabolic cue, and we identify a bottom-up signaling axis through which changes in the PMF trigger AMPK activity in neurons to promote foraging behavior.

Titan mice as a model to test interventions that attenuate frailty and increase longevity.

Wild-type murine models for aging research have lifespans of several years, which results in long experimental duration and late output. Here we explore the short-lived non-inbred Titan mouse (DU6) as a mouse model to test longevity interventions. We show that Titan mice exhibit increased frailty and senescence-associated beta-galactosidase activity at an early age. Dietary intervention attenuates the frailty progression of Titan mice. Additionally, cyclic administration of the senolytic drug Navitoclax at an early age increases the lifespan and reduces senescence-associated beta-galactosidase activity. Our data suggests that Titan mice can serve as a cost-effective and timely model for longevity interventions in mammals.

All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.

Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.

Mitochondrial dysfunction plays a central role in aging but the exact biological causes are still being determined. Here, we show that optogenetically increasing mitochondrial membrane potential during adulthood using a light-activated proton pump improves age-associated phenotypes and extends lifespan in C. elegans. Our findings provide direct causal evidence that rescuing the age-related decline in mitochondrial membrane potential is sufficient to slow the rate of aging and extend healthspan and lifespan.

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse.

Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The non-inbred mouse (Mus musculus) line Titan, also known as DU6, is one of the world's longest selection experiments for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study further characterizes the geno- and phenotypes of this non-inbred mouse line and tests its suitability as an interventional obesity model. In contrast to previous findings, our data suggest that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice also show modifications in the liver transcriptome, proteome, and epigenome linked to metabolic (dys)regulations. Importantly, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.

The Brain Epigenome Goes Drunk: Alcohol Consumption Alters Histone Acetylation and Transcriptome.

Recent studies demonstrated that alcohol consumption can induce epigenetic changes in the brain, although the exact mechanism underlying such changes remained unclear. Now, a report by Mews et al. shows a direct link between alcohol consumption and histone acetylation changes in the brain, which are mediated by the neuronal acetyl-CoA synthase, ACSS2.

Measuring and Interpreting Oxygen Consumption Rates in Whole Fly Head Segments.

Regulated metabolic activity is essential for the normal functioning of living cells. Indeed, altered metabolic activity is causally linked with the progression of cancer, diabetes, neurodegeneration, and aging to name a few. For instance, changes in mitochondrial activity, the cell's metabolic powerhouse, have been characterized in many such diseases. Generally, the oxygen consumption rates of mitochondria were considered a reliable readout of mitochondrial activity and measurements in some of these studies were based on isolated mitochondria or cells. However, such conditions may not represent the complexity of a whole tissue. Recently, we have developed a novel method that enables the dynamic measurement of oxygen consumption rates from whole isolated fly heads. By utilizing this method, we have recorded lower oxygen consumption rates of the whole head segment in young versus aged flies. Secondly, we have discovered that lysine deacetylase inhibitors rapidly alter the oxygen consumption in the whole head. Our novel technique may therefore aid in uncovering new properties of various drugs, which may impact metabolic rates. Furthermore, our method may give a better understanding of metabolic behavior in an experimental setup that more closely resembles physiological states.