Biology subjects

Catrow, J. L.

Publications and source records attributed to Catrow, J. L..

4 recordsLinked to original sources

bioRxiv2026

Induction and regulation of a reversible form of suspended animation in C. elegans

Suspended animation, a state of extreme quiescence with microscopically invisible movement and development, is a remarkable yet poorly understood stress resilience strategy in animals. Here, we describe a newly discovered form of suspended animation inducible by high-population density in isosmotic liquids in C. elegans throughout larval development and adulthood. Transcriptomic, metabolomic and live-cell activity reporter imaging analyses reveal striking molecular and cellular landscape changes by such liquid-induced suspended animation (LISA), including remodeling of gene expression programs, energy metabolites, lysosomal and mitochondrial morphology. Genetic screens identify mutants with altered stress responses and survival against LISA. While key endo-lysosomal regulators promote survival during LISA, organelle remodeling and a neuronal axis via downstream neuropeptide and cAMP/PKA signaling orchestrate behavioral awakening from LISA. Our findings define a facile paradigm for reversible SA, providing a powerful model system to uncover key molecular and cellular mechanisms governing an extreme case of reversible life arrest and dormancy.

developmental biology↗

bioRxiv2025

STING and VDAC inhibitors attenuate inflammation and ineffective erythropoiesis caused by an altered metabolome in the Nan (EKLF/E339D) mouse model of neonatal anemia

Erythroid Kruppel-like factor (EKLF/KLF1) is an essential transcriptional regulator of all aspects of erythropoiesis. The mouse neonatal anemia (Nan) mutation is driven by a semi-dominant mutation in one allele of the EKLF second Zn-finger at position E339D. RNA-seq analysis of Nan/+ erythroid cells showed that expression of numerous enzymes associated with metabolic pathways are changed as a result. We assessed and analyzed the effects of this dysregulation by mass spectrometry of embryonic and adult material. Our results show that mono-allelic expression of Nan-EKLF has profound impacts on erythroid cell metabolism: levels of amino acids, nucleotides, and metabolites are altered, more energy is needed for survival and proliferation, and glucose is taken up more rapidly. As a result, mitochondrial morphology is distorted, leading to VDAC1 oligomerization and mtDNA release to the cytosol. This activates the cGAS-STING signaling pathway and induces a type-I IFN response that drives inflammation. Use of STING or VDAC inhibitors alleviates these conditions both ex vivo and in vivo. Mechanistically, treatment restores normal erythroid cell divisions and differentiation, and decreases inflammatory pathways in the bone marrow. Our findings are likely directly relevant to the dyserythropoiesis observed in CDA type IV patients that carry a similar mutation.

molecular biology↗

bioRxiv2024

Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites IIIQO and IIF of the electron transport chain, reduced the formation of I+III2+IV respiratory supercomplex, and disrupted the propensity of coenzyme Q (CoQ) to become reduced. Thus, low mitochondrial CL disrupts electron transport chain to promote oxidative stress and contributes to pathogenesis of MASH.

biochemistry↗

bioRxiv2024

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/Slc16a1). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

biochemistry↗