Biology subjects

Ramanathan, C.

Publications and source records attributed to Ramanathan, C..

5 recordsLinked to original sources

bioRxiv2026

Mycoplasma gallisepticum uses itaconate-associated mitochondrial inhibition to suppress host immunometabolism

Many pathogens actively suppress early host immune responses to enhance their fitness. Mitochondria function as key regulators of immune activation, yet whether pathogens suppress host immunity by manipulating mitochondrial metabolism in vivo remains largely unknown. During an innate immune response, the metabolite itaconate increases in abundance and acts as an immunomodulator, due to its inhibition of succinate dehydrogenase (SDH), a key mitochondrial regulator of cellular immunity. We hypothesized that Mycoplasma gallisepticum (MG), a recently emerged pathogen of wild songbirds, most notably house finches (Haemorhous mexicanus), suppresses early host immune responses by limiting SDH-dependent immune activation via itaconate. We tested these hypotheses using experimental 3-day infection of finches with heat-killed MG, live MG or pharmacological elevation of the SDH inhibitor itaconate. Following inoculation, we quantified intracellular itaconate and mitochondrial respiratory function in peripheral blood mononuclear cells (PBMCs) and pro-inflammatory cytokine gene expression in erythrocytes, in addition to infected tissues (trachea and conjunctiva). Heat-killed MG increased SDH-dependent mitochondrial respiration in PBMCs and cytokine gene expression in erythrocytes, but live MG did not show these increases, but revealed increased itaconate accumulation in PBMCs. Dimethyl itaconate administration reproduced the suppressed metabolic and immune phenotype in blood cells observed with live MG, suggesting an itaconate-associated mechanism. In contrast, live MG increased mitochondrial respiration and gene expression levels of cytokines in eyelid conjunctiva, whereas other treatments did not. These findings indicate that MG suppresses host metabolic and cytokine signaling in systemically circulating immune cells through a mechanism consistent with itaconate-mediated inhibition of SDH-dependent mitochondrial respiration, while still inducing an inflammatory response at the site of infection. Our data suggest that MG, like other pathogens, can commandeer host immunometabolic pathways during infection to their benefit and that mitochondria are a key site of competition between host and pathogen.

immunology↗

bioRxiv2025

The mPFC molecular clock mediates the effects of sleep deprivation on depression-like behavior and regulates sleep consolidation and homeostasis

Disruptions in sleep, circadian rhythms, and neural plasticity are closely linked to the pathophysiology and treatment of depression. Acute sleep deprivation (SD) produces rapid but transient antidepressant effects, yet the underlying mechanisms remain poorly understood. Using a mouse model of stress-induced depression, we found altered sleep architecture, impaired sleep homeostasis, and disrupted day-night oscillations of the markers of glutamatergic plasticity - Homer1a and synaptic AMPAR expression in the medial prefrontal cortex (mPFC). These changes were accompanied by a blunted homeostatic response to SD. We further show that SD and ketamine, both rapid-acting antidepressants, exert opposing effects on mPFC circadian gene expression: SD enhances the expression of negative clock loop genes (e.g., Per, Cry), mirroring stress effects, while ketamine downregulates these same genes. Targeted deletion of the core clock gene Bmal1 in CaMK2a-expressing excitatory neurons of the mPFC disrupted sleep-wake architecture, elevated slow-wave activity, and abolished the behavioral and molecular (Homer1a) response to SD. Additionally, pharmacological activation of the clock repressor REV-ERB suppressed the antidepressant effects of SD. Our results demonstrate that the mPFC molecular clock is essential for the regulation of sleep consolidation and homeostasis, and mediates the effects of SD on behavior.

neuroscience↗

bioRxiv2024

Mycoplasma gallisepticum (MG) infection inhibits mitochondrial respiratory function in a wild songbird

An animals immune function is vital for survival, but some pathogens could manipulate their hosts immune and metabolic responses. One example is Mycoplasma gallisepticum (MG), which infects both the respiratory system and conjunctiva of the eye in house finches (Haemorhous mexicanus). MG has been shown to exhibit immune- and metabolic-suppressive properties, but the physiological mechanisms underlying these properties are still unknown. Recent studies demonstrated that mitochondria could serve as powerhouses for both ATP production and immunity, notably inflammatory processes, through regulating complex II and its metabolites. Consequently, in this study, we investigate the short-term (3d post inoculation) and long-term (34d post inoculation) effects of MG infection on the hepatic mitochondrial respiration of house finches from two populations and infected with two different MG isolates. After short-term infection, MG-infected birds had significantly lower state 2 and state 4 respiration, but only when using complex II substrates. After long-term infection, MG-infected birds exhibited lower state 3 respiration with both complex I and II substrates, resulting in lower respiratory control ratio compared to uninfected controls, which aligned with the hypothesized metabolic-suppressive properties of MG. Interestingly, mitochondrial respiration showed limited differences with house finch population of origin, MG isolate, and whether birds were recovered from infection or not. We propose that MG may target mitochondrial complex II for its immune-suppressive properties during the early stages of infection and inhibit mitochondrial respiration for its metabolic-suppressive properties at later stage of infection, both of which should delay recovery of the host and extend infectious periods.

physiology↗

bioRxiv2023

Captivity affects mitochondrial aerobic respiration and carotenoid metabolism in the house finch (Haemorhous mexicanus)

In many species of animals, red carotenoid-based coloration is produced by metabolizing yellow dietary pigments, and this red ornamentation is an honest signal of individual quality. However, the physiological basis for associations between organism function and the metabolism of red ornamental carotenoids from yellow dietary carotenoids remains uncertain. A recent hypothesis posits that carotenoid metabolism depends on mitochondrial performance, with diminished red coloration resulting from altered mitochondrial aerobic respiration. To test for an association between mitochondrial respiration and red carotenoids, we held wild-caught, molting male house finches in either small bird cages or large flight cages to create environmental challenges during the period when red ornamental coloration is produced. We predicted that small cages would present a less favorable environment than large flight cages and that captivity would affect both mitochondrial performance and the abundance of red carotenoids. We found no evidence that living in small versus large cages had significant effects on wild-caught house finches; however, birds in cages of any size circulated fewer red carotenoids, showed increased mitochondrial respiratory rates, and had lower complex II respiratory control ratios--a metric associated with mitochondrial efficiency--compared to free-living birds. Moreover, among captive individuals, the birds that circulated the most red carotenoids had the highest mitochondrial respiratory control ratio for complex II substrates. These data support the hypothesis that the metabolism of red carotenoid pigments is linked to mitochondrial aerobic respiration in the house finch, but the mechanisms for this association remain to be established. SUMMARY STATEMENTHolding wild-caught male house finches in cages exposed a relationship between red carotenoid production and mitochondrial respiratory efficiency.

evolutionary biology↗

bioRxiv2021

Naked mole-rat and Damaraland mole-rat exhibit lower respiration in mitochondria, cellular and organismal levels

Naked mole-rats (NMR) and Damaraland mole-rats (DMR) are the only two eusocial mammals known. Both species exhibit extraordinary longevity for their body size, high tolerance to hypoxia and oxidative stress and high reproductive output; these collectively defy the concept that all life-history traits should be negatively correlated. However, when life-history traits share similar underpinning physiological mechanisms, these may be positively associated with each other. Here, we propose that the bioenergetic properties of mole-rats share a potential common mechanism. We adopted a top-down perspective measuring the bioenergetic properties at the organismal, cellular, and molecular level in both species and the biological significance of these properties were compared with the same measures in Siberian hamsters and C57BL/6 mice, chosen for their similar body size to the mole-rat species. We found mole-rats shared several bioenergetic properties that differed from their comparator species, including low basal metabolic rates, a high dependence on glycolysis rather than on oxidative phosphorylation for ATP production, and low proton conductance across the mitochondrial inner membrane. These shared mole-rat features could be a result of evolutionary adaptation to tolerating variable oxygen atmospheres, in particular hypoxia, and may in turn be one of the molecular mechanisms underlying their extremely long lifespans.

physiology↗