Biology subjects

Ryan, T. A.

Publications and source records attributed to Ryan, T. A..

22 records · Page 2Linked to original sources

bioRxiv2020

Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals

The human brain is a uniquely vulnerable organ as interruption in fuel supply leads to acute cognitive impairment on rapid time scales. The reasons for this vulnerability are not well understood, but nerve terminals are likely loci of this vulnerability as they do not store sufficient ATP molecules and must synthesize them on-demand during activity or suffer acute degradation in performance. The requirements for on-demand ATP synthesis however depends in part on the magnitude of resting metabolic rates. We show here that, at rest, synaptic vesicle (SV) pools are a major source of presynaptic basal energy consumption. This basal metabolism arises from SV-resident V-ATPases compensating for a hidden resting H+ efflux from the SV lumen. We show that this steady-state H+ efflux is 1) mediated by vesicular neurotransmitter transporters, 2) independent of the SV cycle, 3) accounts for ~half of the resting synaptic energy consumption and 4) contributes to nerve terminal intolerance of fuel deprivation. O_LINerve terminals consume large amounts of ATP even at rest C_LIO_LIA large fraction of the resting metabolic burden arises from the V-ATPase C_LIO_LISteady-state V-ATPase activity is driven by a synaptic vesicle H+ leak C_LIO_LIThis H+ leak is mediated vesicular neurotransmitter transporters C_LI

neuroscience↗

bioRxiv2019

Plumage manipulation alters the integration of social behavior, physiology, internal microbiome, and fitness.

Signals often covary with physiological and behavioral traits to form an axis of integrated phenotypic variation associated with reproductive performance. This pattern of phenotypic integration could result from intrinsic between-individual differences that are causally related to signal production, physiology, and behavior. Alternatively, signal expression itself might generate dynamic feedback between physiology, behavior, and the experienced social environment, resulting in an integrated phenotype. Here, we manipulated the plumage of female tree swallows (Tachycineta bicolor) to decouple the expression of a social signal from any pre-existing behavioral or physiological differences. We collected a time series of physiological samples, monitored social interactions with a sensor network, and tracked reproductive performance. Relative to sham controls, dulled females experienced an altered social environment; overall, these females were visited more by conspecific females and less by males. Dulled females subsequently changed their own behavior by initiating fewer interactions and increasing nestling provisioning. These differences resulted in an altered internal microbiome and glucose levels and, ultimately, dulled females produced more offspring. Moreover, dulled females produced larger clutches than control females in the year after the manipulation. Thus, signal variation alone--independent from any pre-existing differences--had a sustained causal affect on a suite of integrated traits. This finding suggests that dynamic feedback may play an important role in coordinating an integrated signaling phenotype. Our results have implications for understanding how variation in signal expression arises and is maintained and the extent to which the information encoded in signals is contingent upon their use in a social environment.

zoology↗

bioRxiv2019

Molecular tuning of the axonal mitochondrial Ca2+ uniporter ensures metabolic flexability of neurotransmission

The brain is a vulnerable metabolic organ and must adapt to different fuel conditions to sustain function. Nerve terminals are a locus of this vulnerability but how they regulate ATP synthesis as fuel conditions vary is unknown. We show that synapses can switch from glycolytic to oxidative metabolism, but to do so, they rely on activity-driven presynaptic mitochondrial Ca2+ uptake to accelerate ATP production. We demonstrate that while in non-neuronal cells mitochondrial Ca2+ uptake requires elevated extramitochondrial Ca2+, axonal mitochondria readily take up Ca2+ in response to small changes in Ca2+. We identified the brain-specific protein MICU3 as a critical driver of this tuning of Ca2+ sensitivity. Ablation of MICU3 renders axonal mitochondria similar to non-neuronal mitochondria, prevents acceleration of local ATP synthesis, and impairs presynaptic function under oxidative conditions. Thus, presynaptic mitochondria rely on MICU3 to facilitate mitochondrial Ca2+ uptake during activity and achieve metabolic flexibility.\n\nO_LISynapses rely on activity-driven mitochondrial ATP synthesis with oxidative fuels\nC_LIO_LIMitochondrial Ca2+ uptake is required to stimulate ATP synthesis in axons\nC_LIO_LIThe mitochondria Ca2+ uptake threshold is lower in axons than in non-neuronal cells\nC_LIO_LIMICU3 controls the Ca2+ sensitivity of MCU in axonal mitochondria\nC_LI

neuroscience↗

bioRxiv2017

Actin enhances ER-mitochondrial calcium transfer and IMM constriction during mitochondrial division

Mitochondrial division requires division of both the inner and outer mitochondrial membranes (IMM and OMM, respectively). Interaction with endoplasmic reticulum (ER) promotes OMM division by recruitment of the dynamin Drp1, but effects on IMM division are not well characterized. We previously showed that actin polymerization through the ER-bound formin INF2 stimulates Drp1 recruitment in mammalian cells. Here, we show that INF2-mediated actin polymerization stimulates a second mitochondrial response independent of Drp1: a rise in mitochondrial matrix calcium through the mitochondrial calcium uniporter. ER stores supply the increased mitochondrial calcium, and the role of actin is to increase ER-mitochondria contact. Myosin IIA is also required for this mitochondrial calcium increase. Elevated mitochondrial calcium in turn activates IMM constriction in a Drp1-independent manner. IMM constriction requires electron transport chain activity. IMM division precedes OMM division. These results demonstrate that actin polymerization independently stimulates the dynamics of both membranes during mitochondrial division: IMM through increased matrix calcium, and OMM through Drp1 recruitment.

cell biology↗