Intracellular Lactate Dynamics Reveal the Metabolic Diversity of Glutamatergic Neurons.

Lactate, an intermediary between glycolysis and mitochondrial oxidative phosphorylation, reflects the metabolic state of neurons. Here, we utilized a genetically-encoded lactate FRET biosensor to uncover subpopulations of distinct metabolic states among glutamatergic neurons. Neurons within specific subpopulations exhibited correlated lactate flux patterns that stemmed from inherent cellular properties rather than neuronal interconnectivity.

Drosophila tweety facilitates autophagy to regulate mitochondrial homeostasis and bioenergetics in Glia.

Mitochondria support the energetic demands of the cells. Autophagic turnover of mitochondria serves as a critical pathway for mitochondrial homeostasis. It is unclear how bioenergetics and autophagy are functionally connected.

Regulation of Aging and Longevity by Ion Channels and Transporters.

Despite significant advances in our understanding of the mechanisms that underlie age-related physiological decline, our ability to translate these insights into actionable strategies to extend human healthspan has been limited. One of the major reasons for the existence of this barrier is that with a few important exceptions, many of the proteins that mediate aging have proven to be undruggable. The argument put forth here is that the amenability of ion channels and transporters to pharmacological manipulation could be leveraged to develop novel therapeutic strategies to combat aging.

p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of .

Inhibition of TRPML1, which is encoded by , is known to deter cell proliferation in various malignancies. Here, we report that the tumor suppressor, p53, represses in the urothelium such that either the constitutive loss or ectopic knockdown of -in both healthy and bladder cancer cells-increased expression. Conversely, nutlin-mediated activation of p53 led to the repression of .

Irritability in Huntington's Disease.

Huntington's disease (HD) is a heritable and fatal neurodegenerative disease characterized by a triad of motor, cognitive and neuropsychiatric symptoms. A common and particularly detrimental neuropsychiatric alteration in HD gene carriers is irritability, which frequently manifests as abrupt and unpredictable outbursts of anger. This symptom increases the burden of HD in multiple ways, such as jeopardizing employment and straining familial or caregiver support.

Roles for the Endoplasmic Reticulum in Regulation of Neuronal Calcium Homeostasis.

By influencing Ca homeostasis in spatially and architecturally distinct neuronal compartments, the endoplasmic reticulum (ER) illustrates the notion that form and function are intimately related. The contribution of ER to neuronal Ca homeostasis is attributed to the organelle being the largest reservoir of intracellular Ca and having a high density of Ca channels and transporters. As such, ER Ca has incontrovertible roles in the regulation of axodendritic growth and morphology, synaptic vesicle release, and neural activity dependent gene expression, synaptic plasticity, and mitochondrial bioenergetics.

TRPing the homeostatic alarm - Melanoma cells are selectively vulnerable to TRPML1 deletion.

To thrive in otherwise inhospitable conditions, cancer cells utilize endolysosomes to impose homeostatic control over cellular metabolism and growth. In a recent study, Kasitinon et al. demonstrate a requirement for the endolysosomal channel, TRPML1, in proliferation and survival of melanoma cells.

TRPML1 and RAS-driven cancers - exploring a link with great therapeutic potential.

Activating mutations in the family of proto-oncogenes represent some of the leading causes of cancer. Unmitigated proliferation of cells harboring oncogenic mutations is accompanied by a massive increase in cellular bioenergetic demands, which offers unique opportunities for therapeutic intervention. To withstand the steep requirements for metabolic intermediates, RAS-driven cancer cells enhance endolysosome and autophagosome biogenesis.

Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets.