Last update 19 Sep 2024

MTFP1

Last update 19 Sep 2024

Basic Info

Synonyms

HSPC242, Mitochondrial 18 kDa protein, mitochondrial fission process 1

+ [3]

Introduction

Involved in the mitochondrial division probably by regulating membrane fission. Loss-of-function induces the release of cytochrome c, which activates the caspase cascade and leads to apoptosis.

Drugs associated with MTFP1

MTC-1203

Target

DNM1L x MTFP1

Mechanism

DNM1L modulators [+1]

Active Org.

Mitoconix Bio Ltd.

Originator Org.

Stanford University

Active Indication

Alzheimer Disease [+2]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MTFP1

100 Translational Medicine associated with MTFP1

0 Patents (Medical) associated with MTFP1

Literatures (Medical) associated with MTFP1

23 Jul 2024·Proceedings of the National Academy of Sciences

Direct observation correlates NFκB cRel in B cells with activating and terminating their proliferative program

Article

Author: Hoffmann, Alexander ; Chen, Yijia ; Roy, Koushik ; Vaidehi Narayanan, Haripriya ; Xiang, Mark Y ; Roy, Sukanya ; Makkar, Himani ; Huang, Helen

Antibody responses require the proliferative expansion of B cells controlled by affinity-dependent signals. Yet, proliferative bursts are heterogeneous, varying between 0 and 8 divisions in response to the same stimulus. NFκB cRel is activated in response to immune stimulation in B cells and is genetically required for proliferation. Here, we asked whether proliferative heterogeneity is controlled by natural variations in cRel abundance. We developed a fluorescent reporter mTFP1-cRel for the direct observation of cRel in live proliferating B cells. We found that cRel is heterogeneously distributed among naïve B cells, which are enriched for high expressors in a heavy-tailed distribution. We found that high cRel expressors show faster activation of the proliferative program, but do not sustain it well, with population expansion decaying earlier. With a mathematical model of the molecular network, we showed that cRel heterogeneity arises from balancing positive feedback by autoregulation and negative feedback by its inhibitor IκBε, confirmed by mouse knockouts. Using live-cell fluorescence microscopy, we showed that increased cRel primes B cells for early proliferation via higher basal expression of the cell cycle driver cMyc. However, peak cMyc induction amplitude is constrained by incoherent feedforward regulation, decoding the fold change of cRel activity to terminate the proliferative burst. This results in a complex nonlinear, nonmonotonic relationship between cRel expression and the extent of proliferation. These findings emphasize the importance of direct observational studies to complement gene knockout results and to learn about quantitative relationships between biological processes and their key regulators in the context of natural variations.

01 Jul 2024·Cell

MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels

Article

Author: Chinnery, Patrick F ; Villar-Azpillaga, Jara ; Segawa, Mayuko ; Burr, Stephen P ; Petkevicius, Kasparas ; Viegas, Filipa ; Anand, Hanish ; Frison, Michele ; Chowdhury, Suvagata R ; Nie, Yu ; Johnson, Mark ; Paupe, Vincent ; Prudent, Julien ; Tábara, Luis Carlos

Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.

01 Jul 2024·Phytomedicine

SIRT1-activating butein inhibits arecoline-induced mitochondrial dysfunction through PGC1α and MTP18 in oral cancer

Article

Author: Mishra, Soumya Ranjan ; Behera, Bishnu Prasad ; Patil, Shankargouda ; Mahapatra, Kewal Kumar ; Bhutia, Sujit Kumar ; Efferth, Thomas

BACKGROUNDMitochondrial dysfunction associated with mitochondrial DNA mutations, enzyme defects, generation of ROS, and altered oxidative homeostasis is known to induce oral carcinogenesis during exposure to arecoline. Butein, a natural small molecule from Butea monosperma, possesses anti-inflammatory, anti-diabetic, and anti-cancer effects. However, the role of butein in the mitochondrial quality control mechanism has not been illuminated clearly.PURPOSEThis study aimed to explore the role of butein in preserving mitochondrial quality control during arecoline-induced mitochondrial dysfunction in oral cancer to curtail the early onset of carcinogenesis.METHODSCell viability was evaluated by MTT assay. The relative protein expressions were determined by western blotting. Immunofluorescence and confocal imaging were used to analyze the relative fluorescence and co-localization of proteins. Respective siRNAs were used to examine the knockdown-based studies.RESULTSButein, in the presence of arecoline, significantly caused a decrease in mitochondrial hyperpolarization and ROS levels in oral cancer cells. Mechanistically, we found an increase in COXIV, TOM20, and PGC1α expression during butein treatment, and inhibition of PGC1α blunted mitochondrial biogenesis and decreased the mitochondrial pool. Moreover, the fission protein MTP18, and its molecular partners DRP1 and MFF were dose-dependently increased during butein treatment to maintain mitochondria mass. In addition, we also found increased expression of various mitophagy proteins, including PINK1, Parkin, and LC3 during butein treatment, suggesting the clearance of damaged mitochondria to maintain a healthy mitochondrial pool. Interestingly, butein increased the activity of SIRT1 to enhance the functional mitochondrial pool, and inhibition of SIRT1 found to reduce the mitochondrial levels, as evident from the decrease in the expression of PGC1α and MTP18 in oral cancer cells.CONCLUSIONOur study proved that SIRT1 maintains a functional mitochondrial pool through PGC1α and MTP18 for biogenesis and fission of mitochondria during arecoline exposure and could decrease the risk of mitochondria dysfunctionality associated with the onset of oral carcinogenesis.

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MTFP1

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