Mitochondrial morphology regulatory proteins interact with signaling pathways involved in differentiation. In Drosophila oogenesis, EGFR signaling regulates mitochondrial fragmentation in posterior ...follicle cells (PFCs). EGFR driven oocyte patterning and Notch signaling mediated differentiation are abrogated when PFCs are deficient for the mitochondrial fission protein Drp1. It is not known whether fused mitochondrial morphology in drp1 mutant PFCs exerts its effects on these signaling pathways through a change in mitochondrial electron transport chain (ETC) activity. In this study we show that aggregated mitochondria in drp1 mutant PFCs have increased mitochondrial membrane potential. We perform experiments to assess the signaling pathway regulating mitochondrial membrane potential and how this impacts follicle cell differentiation. We find that drp1 mutant PFCs show increase in phosphorylated ERK (dpERK) formed downstream of EGFR signaling. ERK regulates high mitochondrial membrane potential in drp1 mutant PFCs. PFCs depleted of ERK and drp1 are able to undergo Notch mediated differentiation. Notably mitochondrial membrane potential decrease via ETC inhibition activates Notch signaling at an earlier stage in wild type and suppresses the Notch signaling defect in drp1 mutant PFCs. Thus, this study shows that the EGFR pathway maintains mitochondrial morphology and mitochondrial membrane potential in follicle cells for its functioning and decrease in mitochondrial membrane potential is needed for Notch mediated differentiation.
•Aggregated mitochondria in drp1 mutant PFCs have higher membrane potential Ψm.•ERK regulates Ψm in wild type and drp1 mutant cells.•Ψm decrease does not impact EGFR signaling driven oocyte patterning.•Ψm decrease activates Notch signaling in wild type and drp1 mutant cells.
Steady-state mitochondrial structure or morphology is primarily maintained by a balance of opposing fission and fusion events between individual mitochondria, which is collectively referred to as ...mitochondrial dynamics. The details of the bidirectional relationship between the status of mitochondrial dynamics (structure) and energetics (function) require methods to integrate these mitochondrial aspects. To study the quantitative relationship between the status of mitochondrial dynamics (fission, fusion, matrix continuity and diameter) and energetics (ATP and redox), we have developed an analytical approach called mito-SinCe
After validating and providing proof of principle, we applied mito-SinCe
on ovarian tumor-initiating cells (ovTICs). Mito-SinCe
analyses led to the hypothesis that mitochondria-dependent ovTICs interconvert between three states, that have distinct relationships between mitochondrial energetics and dynamics. Interestingly, fusion and ATP increase linearly with each other only once a certain level of fusion is attained. Moreover, mitochondrial dynamics status changes linearly with ATP or with redox, but not simultaneously with both. Furthermore, mito-SinCe
analyses can potentially predict new quantitative features of the opposing fission versus fusion relationship and classify cells into functional classes based on their mito-SinCe
states.This article has an associated First Person interview with the first author of the paper.
Spermatozoa are cells distinctly different from other somatic cells of thebody, capacitation being one of the unique phenomena manifested by thisgamete. We have shown earlier that dihydrolipoamide ...dehydrogenase, apost-pyruvate metabolic enzyme, undergoes capacitation-dependent tyrosinephosphorylation, and the functioning of the enzyme is required forhyperactivation (enhanced motility) and acrosome reaction of hamsterspermatozoa (Mitra, K., and Shivaji, S. (2004) Biol. Reprod. 70,887–899). In this report we have investigated the localization of thismitochondrial enzyme in spermatozoa revealing non-canonicalextra-mitochondrial localization of the enzyme in mammalian spermatozoa. Inhamster spermatozoa, dihydrolipoamide dehydrogenase along with its hostcomplex, the pyruvate dehydrogenase complex, are localized in the acrosome andin the principal piece of the sperm flagella. The localization ofdihydrolipoamide dehydrogenase, however, appears to be in the mitochondria inthe spermatocytes, but in spermatids it appears to show a juxtanuclearlocalization (like Golgi). The capacitation-dependent time course of tyrosinephosphorylation of dihydrolipoamide dehydrogenase appears to be different inthe principal piece of the flagella and the acrosome in hamster spermatozoa.Activity assays of this bi-directional enzyme suggest a strong correlationbetween the tyrosine phosphorylation and the bi-directional enzyme activity.This is the first report of a direct correlation of the localization, tyrosinephosphorylation, and activity of the important metabolic enzyme,dihydrolipoamide dehydrogenase, implicating dual involvement and regulation ofthe enzyme during sperm capacitation.
Mitochondrial dysfunction causes severe congenital cardiac abnormalities and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect ...cardiogenesis poses a major barrier for the development of clinical applications that target mitochondrial deficiency-induced inborn cardiomyopathies. Mitochondrial morphology, which is regulated by fission and fusion, plays a key role in determining mitochondrial activity. Dnm1l encodes a dynamin-related GTPase, Drp1, which is required for mitochondrial fission. To investigate the role of Drp1 in cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Dnm1l in second heart field-derived structures. Mutant cardiomyocytes in the right ventricle (RV) displayed severe defects in mitochondrial morphology, ultrastructure and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes and embryonic lethality. By characterizing this model, we reveal an AMPK-SIRT7-GABPB axis that relays the reduced cellular energy level to decrease transcription of ribosomal protein genes in cardiomyocytes. We therefore provide the first genetic evidence in mouse that Drp1 is essential for RV development. Our research provides further mechanistic insight into how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.
Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated protein (STRAP) is elevated in ...CRCs and is associated with poor outcomes. We investigated the role of STRAP in Apc mutation–induced intestinal tumor initiation and progression.
We generated Strap intestinal epithelial knockout mice (StrapΔIEC) by crossing mice containing floxed alleles of Strap (Strapfl/fl) with Villin-Cre mice. Then we generated ApcMin/+;Strapfl/fl;Vill-Cre (ApcMin/+;StrapΔIEC) mice for RNA-sequencing analyses to determine the mechanism of function of STRAP. We used human colon cancer cell lines (DLD1, SW480, and HT29) and human and mouse colon tumor–derived organoids for STRAP knockdown and knockout and overexpression experiments.
Strap deficiency extended the average survival of ApcMin/+ mice by 80 days and decreased the formation of intestinal adenomas. Expression profiling revealed that the intestinal stem cell signature, the Wnt/β-catenin signaling, and the MEK/ERK pathway are down-regulated in Strap-deficient adenomas and intestinal organoids. Correlation studies suggest that these STRAP-associated oncogenic signatures are conserved across murine and human colon cancer. STRAP associates with MEK1/2, promotes binding between MEK1/2 and ERK1/2, and subsequently induces the phosphorylation of ERK1/2. STRAP activated Wnt/β-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/β-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the β-catenin/TCF4 complex on the Strap promoter.
STRAP is a target of, and is required in, Apc mutation/deletion-induced intestinal tumorigenesis through a novel feed-forward STRAP/MEK-ERK/Wnt-β-catenin/STRAP regulatory axis.
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A cellular protein that mediates intestinal tumor initiation and progression and that can be targeted for anti-tumor response.
In future, increase in the number of healthcare professionals is dependent on the career interest among present undergraduate medical students. Based on their interest to pursue their specialty, the ...availability of medical doctors in each specialty could be done.
This study was to find out future career interest and factors that influence undergraduate medical students to choose their future specialization.
The study was carried out among first-year medical students from five countries. The students were asked to complete an 8-item questionnaire. Two thousand one hundred fifty three participants were enrolled in the study. Data were analyzed in Microsoft-Excel and Statistical Package for the Social Sciences.
Of the 2153 participants, only 1470 responded. Among the 1470 participants, 169 participants were excluded due to the ambiguity in responses, finally making it to 1301participants. Among them, Anatomy (49.3%) followed by Biochemistry (26.7%) and Physiology (24%) were the most preferred subjects.
Anatomy was the most preferred basic science subject among the other subjects and the students were interested to pursuing surgery in future. Furthermore, the most preferred future specialties were surgery, internal medicine and pediatrics with gender variations; males preferring surgery and females in obstetrics and gynecology.
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