Mitochondria as Cellular and Organismal Signaling Hubs.

Mitochondria are traditionally known as the powerhouse of the cell, but their functions extend far beyond energy production. They are vital in cellular and organismal pathways that direct metabolism, stress responses, immunity, and cellular fate. To accomplish these tasks, mitochondria have established networks of both intra- and extracellular communication. Intracellularly, these communication routes comprise direct contacts between mitochondria and other subcellular components as well as indirect vesicle transport of ions, metabolites, and other intracellular messengers. Extracellularly, mitochondria can induce stress responses or other cellular changes that secrete mitochondrial cytokine (mitokine) factors that can travel between tissues as well as respond to immune challenges from extracellular sources. Here we provide a current perspective on the major routes of communication for mitochondrial signaling, including their mechanisms and physiological impact. We also review the major diseases and age-related disorders associated with defects in these signaling pathways. An understanding of how mitochondrial signaling controls cellular homeostasis will bring greater insight into how dysfunctional mitochondria affect health in disease and aging.

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER.

Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPRER, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-based knockout (KO) screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase (HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stress resistance. The breakdown of the glycosaminoglycan, hyaluronan (HA), by TMEM2 within the extracellular matrix (ECM) altered ER stress resistance independent of canonical UPRER pathways but dependent upon the cell-surface receptor, CD44, a putative HA receptor, and the MAPK cell-signaling components, ERK and p38. Last, and most surprisingly, ectopic expression of human TMEM2 in C. elegans protected animals from ER stress and increased both longevity and pathogen resistance independent of canonical UPRER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.

Olfaction regulates peripheral mitophagy and mitochondrial function.

The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPRMT); however, the contexts for which this regulatory capability evolved are unknown. UPRMT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPRMT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPRMT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin-mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPRMT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.

Glia of C. elegans coordinate a protective organismal heat shock response independent of the neuronal thermosensory circuit.

Aging organisms lose the ability to induce stress responses, becoming vulnerable to protein toxicity and tissue damage. Neurons can signal to peripheral tissues to induce protective organelle-specific stress responses. Recent work shows that glia can independently induce such responses. Here, we show that overexpression of heat shock factor 1 (hsf-1) in the four astrocyte-like cephalic sheath cells of Caenorhabditis elegans induces a non-cell-autonomous cytosolic unfolded protein response, also known as the heat shock response (HSR). These animals have increased lifespan and heat stress resistance and decreased protein aggregation. Glial HSR regulation is independent of canonical thermosensory circuitry and known neurotransmitters but requires the small clear vesicle release protein UNC-13. HSF-1 and the FOXO transcription factor DAF-16 are partially required in peripheral tissues for non-cell-autonomous HSR, longevity, and thermotolerance. Cephalic sheath glial hsf-1 overexpression also leads to pathogen resistance, suggesting a role for this signaling pathway in immune function.

Lysosomal recycling of amino acids affects ER quality control.

Recent work has highlighted the fact that lysosomes are a critical signaling hub of metabolic processes, providing fundamental building blocks crucial for anabolic functions. How lysosomal functions affect other cellular compartments is not fully understood. Here, we find that lysosomal recycling of the amino acids lysine and arginine is essential for proper ER quality control through the UPRER. Specifically, loss of the lysine and arginine amino acid transporter LAAT-1 results in increased sensitivity to proteotoxic stress in the ER and decreased animal physiology. We find that these LAAT-1-dependent effects are linked to glycine metabolism and transport and that the loss of function of the glycine transporter SKAT-1 also increases sensitivity to ER stress. Direct lysine and arginine supplementation, or glycine supplementation alone, can ameliorate increased ER stress sensitivity found in laat-1 mutants. These data implicate a crucial role in recycling lysine, arginine, and glycine in communication between the lysosome and ER.

Hypoxia-inducible factor cell non-autonomously regulates C. elegans stress responses and behavior via a nuclear receptor.

The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of the diverse aspects of HIF-regulated biology remains unknown. We discovered that a HIF target, the C. elegans gene cyp-36A1, is required for numerous HIF-dependent processes, including modulation of gene expression, stress resistance, and behavior. cyp-36A1 encodes a cytochrome P450 enzyme that we show controls expression of more than a third of HIF-induced genes. CYP-36A1 acts cell non-autonomously by regulating the activity of the nuclear hormone receptor NHR-46, suggesting that CYP-36A1 functions as a biosynthetic enzyme for a hormone ligand of this receptor. We propose that regulation of HIF effectors through activation of cytochrome P450 enzyme/nuclear receptor signaling pathways could similarly occur in humans.

The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior.

The modification of behavior in response to experience is crucial for animals to adapt to environmental changes. Although factors such as neuropeptides and hormones are known to function in the switch between alternative behavioral states, the mechanisms by which these factors transduce, store, retrieve, and integrate environmental signals to regulate behavior are poorly understood. The rate of locomotion of the nematode Caenorhabditis elegans depends on both current and past food availability. Specifically, C. elegans slows its locomotion when it encounters food, and animals in a food-deprived state slow even more than animals in a well-fed state. The slowing responses of well-fed and food-deprived animals in the presence of food represent distinct behavioral states, as they are controlled by different sets of genes, neurotransmitters, and neurons. Here we describe an evolutionarily conserved C. elegans protein, VPS-50, that is required for animals to assume the well-fed behavioral state. Both VPS-50 and its murine homolog mVPS50 are expressed in neurons, are associated with synaptic and dense-core vesicles, and control vesicle acidification and hence synaptic function, likely through regulation of the assembly of the V-ATPase complex. We propose that dense-core vesicle acidification controlled by the evolutionarily conserved protein VPS-50/mVPS50 affects behavioral state by modulating neuropeptide levels and presynaptic neuronal function in both C. elegans and mammals.

Cytochrome P450 drives a HIF-regulated behavioral response to reoxygenation by C. elegans.

Oxygen deprivation followed by reoxygenation causes pathological responses in many disorders, including ischemic stroke, heart attacks, and reperfusion injury. Key aspects of ischemia-reperfusion can be modeled by a Caenorhabditis elegans behavior, the O2-ON response, which is suppressed by hypoxic preconditioning or inactivation of the O2-sensing HIF (hypoxia-inducible factor) hydroxylase EGL-9. From a genetic screen, we found that the cytochrome P450 oxygenase CYP-13A12 acts in response to the EGL-9-HIF-1 pathway to facilitate the O2-ON response. CYP-13A12 promotes oxidation of polyunsaturated fatty acids into eicosanoids, signaling molecules that can strongly affect inflammatory pain and ischemia-reperfusion injury responses in mammals. We propose that roles of the EGL-9-HIF-1 pathway and cytochrome P450 in controlling responses to reoxygenation after anoxia are evolutionarily conserved.