Onco Lille

Abstract Background The outer mitochondrial Rho GTPase 1, MIRO1, mediates mitochondrial motility within cells, but implications for vascular smooth muscle cell (VSMC) physiology and its roles in vascular diseases, such as neointima formation following vascular injury are widely unknown. Methods Carotid ligation was performed in an in vivo model of selective Miro1 deletion in smooth muscle cells. VSMC proliferation during the cell cycle and molecular mechanisms of smooth muscle cell proliferation were explored in cultured aortic VSMCs by imaging mitochondrial positioning and cristae structure and assessing the effects on ATP production, metabolic function and interactions with components of the electron transport chain (ETC). MIRO1 expression was analyzed in human coronary arteries, and its function was assessed via knockdown in human coronary artery VSMCs. Results Results revealed strong MIRO1 expression in VSMCs within human atherosclerotic plaques. MIRO1 facilitated VSMC proliferation and neointima formation by regulating mitochondrial positioning and PDGF-stimulated ATP production and respiration, critical for cell-cycle progression at G1/S. Deletion of Miro1 disrupted mitochondrial cristae structure, diminished ETC complex I activity, and impaired super complex formation. Notably, restoring MIRO1 function with a mutant lacking EF hands, which are essential for mitochondrial mobility, only partially rescued these effects. MIRO1 knockdown in human coronary artery VSMCs confirmed its pivotal role in mitochondrial function and VSMC proliferation. Conclusions This study highlights two key mechanisms by which MIRO1 regulates VSMC proliferation. First, it maintains ATP synthesis by preserving mitochondrial cristae integrity. Second, its Ca2+-dependent EF hands enable ATP-dependent mitochondrial positioning. By linking mitochondrial motility and energy production to VSMC physiology, these findings position MIRO1 as a critical regulator of vascular remodeling and a potential target for therapeutic interventions.

Over the few decades, terahertz radiation has attracted attention for its applications in imaging, spectroscopy, communications, and security. Recently, this electromagnetic spectral range became highly interesting for research of quantum materials, as ultra-microscopies are now able to operate at those frequencies. In this work, we demonstrate the use of a cryogen-free compact quantum cascade laser as THz source for scattering scanning near-field microscopy to study the nano-optics of 2D materials such as Bi₂Se₃ and twisted-bilayer graphene. Custom-designed probes with tailored shaft lengths enabled high-contrast imaging at 2.5 THz, achieving spatial resolutions comparable to those in the mid-infrared range and delivering high sensitivity in THz nano-imaging. An in-depth analysis of probe performance across different lengths is also included.

The histone methyltransferase DOT1L (DOT1 like, disruptor of telomeric silencing) is responsible for methylation of H3K79, leading to oncogene transcription, and it is involved in the development of different types of cancers such as MLL-rearranged leukemia (MLL-r, myeloid-lymphoid leukemia). Inhibitors of DOT1L have therapeutic potential. Thus, we present herein the in silico based design and the multi-step synthesis of different series of non-nucleosidic compounds that mimic the S-adenosyl-l-methionine (SAM) cofactor and inhibit DOT1L. The compounds incorporate an aminopyrimidine moiety coupled to a functionalized aryl based on the structure of published DOT1L inhibitors that have entered clinical trials (EPZ-5676, pinometostat). Their DOT1L activity was determined and structure-activity relationships (SARs) were established, leading to the identification of key moieties for the development of DOT1L-selective compounds. To determine their specificity, the activity of the compounds was evaluated on other methyltransferases that also use SAM as a cofactor, such as DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), including the PRC2 complex, G9a, PRMT1, PRMT4 and PRMT5. We identified compound 19d (IC50 = 8.0 μM) as a DNMT3a inhibitor, and 1n (EC50 = 19.0 μM), 1p (EC50 = 4.8 μM) and 19g (EC50 = 11.0 μM) as PRMT4 inhibitors based on the in silico approach that was employed. The in vitro ADMET profile of the compounds matched with the generally accepted lead-like criteria and encouraged the further optimization of these non-nucleosidic hit compounds.