Biology subjects

Mitra, K.

Publications and source records attributed to Mitra, K..

22 records · Page 2Linked to original sources

bioRxiv2021

Fine-tuned repression of Drp1 driven mitochondrial fission primes a slow cycling stem/progenitor-like state towards accelerating neoplastic transformation of keratinocytes

The opposing processes of mitochondrial fission and fusion are emerging as crucial regulators of stemness. Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. However, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Here, we demonstrate that only fine-tuned repression of Drp1 establishes a stem/progenitor-like state towards supporting carcinogen driven neoplastic transformation of keratinocytes, while more complete Drp1 repression prevents it. Only fine-tuned Drp1 repression maintains small networks of fused mitochondria to sustain a unique gene-expression profile with elevated stem/progenitor cell functional markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Cells with such a mitochondria-primed state are slow cycling, susceptible to transformation, and when enriched by mild carcinogen exposure sustains elevated self-renewal/proliferation to form less differentiated tumors. Therefore, our data for the first time highlights a goldilocks level of Drp1 repression that supports stem/progenitor state dependent neoplastic transformation.

cell biology↗

bioRxiv2021

Mitochondrial Fission Regulates Transcription of Ribosomal Protein Genes in Embryonic Hearts

Mitochondrial dysfunction causes severe congenital heart diseases 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 inborn heart defects due to mitochondrial deficiency. Mitochondrial morphology, which is regulated by fission and fusion, plays key roles in determining mitochondrial activity. Drp1 encodes a dynamin-related GTPase required for mitochondrial fission. To investigate the role of mitochondrial fission on cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Drp1 in second heart field derived structures. Deletion of Drp1 in embryonic cardiomyocytes led to severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the mitochondrial fission anomaly to reduced transcription of ribosomal protein genes in mutant cardiomyocytes. We therefore provide the first mouse genetic evidence to show that mitochondrial fission is essential for embryonic heart development. Furthermore, we uncovered a novel signaling cascade that mediates the crosstalk between mitochondrial dysfunction and protein synthesis. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.

developmental biology↗

bioRxiv2019

Mito-SinCe2 Approach to Quantify Relationships between Mitochondrial Dynamics and Energetics status

Mitochondrial dynamics primarily refers to the opposing fission and fusion events between individual mitochondria, which maintains steady-state mitochondrial morphology in cells. The details of the bidirectional relationship between mitochondrial dynamics and energetics are unclear as the methods to integrate these mitochondrial aspects are lacking. To study the quantitative relationship between mitochondrial dynamics (fission, fusion, matrix continuity and diameter) and energetics (ATP and redox), we have developed and validated an analytical approach, mito-SinCe2. Application of this approach led to the hypothesis that mitochondria-dependent ovarian tumor initiating cells interconvert between 3 states with 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 either with ATP or with redox, but not simultaneously with both. Furthermore, mito-SinCe2 analyses can potentially predict new quantitative features of the opposing fission vs. fusion relationship and classify cells into functional classes based on their mito-SinCe2 states.

cell biology↗

bioRxiv2018

S-MiRAGE: A quantitative, secreted RNA-based reporter of gene expression and cell persistence

Non-destructive measurements of cell persistence and gene expression are crucial for longitudinal research studies and for prognostic assessment of cell therapies. Here we describe S-MiRAGE, a platform that utilizes small secreted RNA molecules as sensitive and quantitatively accurate reporters of cellular processes. We demonstrate the utility of S-MiRAGE by monitoring the differentiation status of human embryonic stem cells in vitro, and tumor growth in a mouse model in vivo.

bioengineering↗