Last update 01 Nov 2024

MTFP1

Last update 01 Nov 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·Journal of Neurochemistry

Regulation of astrocyte metabolism by mitochondrial translocator protein 18 kDa

Article

Author: Bamford, Rosemary ; Robb, Josephine L ; Pye, Katherine R ; Firth, Wyn ; Ellacott, Kate L J ; Stewart, Daisy ; Oguro-Ando, Asami ; Beall, Craig

AbstractThe mitochondrial translocator protein 18 kDa (TSPO) has been linked to functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in Leydig cells and microglia indicate that TSPO function may vary between cells depending on their specialized roles. Astrocytes are critical for providing trophic and metabolic support in the brain. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. Relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO‐deficient (TSPO−/−) mouse primary astrocytes in vitro (MPAs) and a human astrocytoma cell line (U373 cells), we performed extracellular metabolic flux analyses. We found that TSPO deficiency reduced basal cellular respiration and attenuated the bioenergetic response to glucopenia. Fatty acid oxidation was increased, and lactate production was reduced in TSPO−/− MPAs and U373 cells. Co‐immunoprecipitation studies revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a in U373 and MPAs, presenting a mechanism wherein TSPO may regulate FAO in these cells. Compared to TSPO+/+ cells, in TSPO−/− MPAs we observed attenuated tumor necrosis factor release following 3 h lipopolysaccharide (LPS) stimulation, which was enhanced at 24 h post‐LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility, TSPO deficiency does not appear to modulate the metabolic response of MPAs to inflammation, at least in response to the model used in this study.

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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 ; Frison, Michele ; Anand, Hanish ; 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.

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MTFP1

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