The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.

Sudden cardiac death (SCD) is a major health concern, which can be the sign of a latent mitochondrial disease. However, mitochondrial DNA (mtDNA) contribution is largely unexplored in SCD at population level. Recently, mtDNA variants have been associated with congenital cardiopathy and higher risk of ischemic heart disease, suggesting them as potential risk factors also in SCD.

Mitochondrial chaperonin DNAJC15 promotes vulnerability to ferroptosis of chemoresistant ovarian cancer cells.

DNAJC15 is a mitochondrial TIMM23-related co-chaperonin known for its role in regulating oxidative phosphorylation efficiency, oxidative stress response and lipid metabolism. Recently, it has been proposed that the loss of DNAJC15 correlates with cisplatin (CDDP)-resistance onset in ovarian cancer (OC), suggesting this protein as a potential prognostic factor during OC progression. However, the molecular mechanisms through which DNAJC15 contributes to CDDP response remains poorly investigated.

Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models.

Background: Mitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted.

Methods: Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels.

A computational study to assess the pathogenicity of single or combinations of missense variants on respiratory complex I.

Variants found in the respiratory complex I (CI) subunit genes encoded by mitochondrial DNA can cause severe genetic diseases. However, it is difficult to establish a priori whether a single or a combination of CI variants may impact oxidative phosphorylation. Here we propose a computational approach based on coarse-grained molecular dynamics simulations aimed at investigating new CI variants.

Downregulation of PLIN2 in human dermal fibroblasts impairs mitochondrial function in an age-dependent fashion and induces cell senescence via GDF15.

Perilipin 2 (PLIN2) is a lipid droplet (LD)-coating protein playing important roles in lipid homeostasis and suppression of lipotoxicity in different tissues and cell types. Recently, a role for PLIN2 in supporting mitochondrial function has emerged. PLIN2 dysregulation is involved in many metabolic disorders and age-related diseases.

NDUFS3 knockout cancer cells and molecular docking reveal specificity and mode of action of anti-cancer respiratory complex I inhibitors.

Inhibition of respiratory complex I (CI) is becoming a promising anti-cancer strategy, encouraging the design and the use of inhibitors, whose mechanism of action, efficacy and specificity remain elusive. As CI is a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is required to avoid side effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI.

MicroRNA and Metabolic Profiling of a Primary Ovarian Neuroendocrine Carcinoma Pulmonary-Type Reveals a High Degree of Similarity with Small Cell Lung Cancer.

Small cell neuroendocrine carcinoma is most frequently found in the lung (SCLC), but it has been also reported, albeit with a very low incidence, in the ovary. Here, we analyze a case of primary small cell carcinoma of the ovary of pulmonary type (SCCOPT), a rare and aggressive tumor with poor prognosis, whose biology and molecular features have not yet been thoroughly investigated. The patient affected by SCCOPT had a residual tumor following chemotherapy which displayed pronounced similarity with neuroendocrine tumors and lung cancer in terms of its microRNA expression profile and mTOR-downstream activation.

Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration.

In mammals, the physiological activation of the glucocorticoid receptor (GR) by glucocorticoids (GCs) promotes the maturation of cardiomyocytes during late gestation, but the effect on postnatal cardiac growth and regenerative plasticity is unclear. Here we demonstrate that the GC-GR axis restrains cardiomyocyte proliferation during postnatal development. Cardiomyocyte-specific GR ablation in conditional knockout (cKO) mice delayed the postnatal cardiomyocyte cell cycle exit, hypertrophic growth and cytoarchitectural maturation.

Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer.

Anticancer strategies aimed at inhibiting Complex I of the mitochondrial respiratory chain are increasingly being attempted in solid tumors, as functional oxidative phosphorylation is vital for cancer cells. Using ovarian cancer as a model, we show that a compensatory response to an energy crisis induced by Complex I genetic ablation or pharmacological inhibition is an increase in the mitochondrial biogenesis master regulator PGC1α, a pleiotropic coactivator of transcription regulating diverse biological processes within the cell. We associate this compensatory response to the increase in PGC1α target gene expression, setting the basis for the comprehension of the molecular pathways triggered by Complex I inhibition that may need attention as drawbacks before these approaches are implemented in ovarian cancer care.

Transcriptomic Analysis of the Dual Response of Rhodococcus aetherivorans BCP1 to Inorganic Arsenic Oxyanions.

Bacterial strains belonging to the genus are able to degrade various toxic organic compounds and tolerate high concentrations of metal(loid)s. We have previously shown that Rhodococcus aetherivorans BCP1 is resistant to various levels of the two arsenic inorganic species, arsenite [As(III)] and arsenate [As(V)]. However, while arsenite showed toxic effects at concentrations as low as 5 mM, arsenate at 30 mM boosted the growth rate of BCP1 cells and was toxic only at concentrations of >100 mM.

New Insights on Rotenone Resistance of Complex I Induced by the m.11778G>A/ Mutation Associated with Leber's Hereditary Optic Neuropathy.

The finding that the most common mitochondrial DNA mutation m.11778G>A/ (p.R340H) associated with Leber's hereditary optic neuropathy (LHON) induces rotenone resistance has produced a long-standing debate, because it contrasts structural evidence showing that the ND4 subunit is far away from the quinone-reaction site in complex I, where rotenone acts.

Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome.

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer.

NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate.

Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3.

A Humanized Bone Niche Model Reveals Bone Tissue Preservation Upon Targeting Mitochondrial Complex I in Pseudo-Orthotopic Osteosarcoma.

A cogent issue in cancer research is how to account for the effects of tumor microenvironment (TME) on the response to therapy, warranting the need to adopt adequate in vitro and in vivo models. This is particularly relevant in the development of strategies targeting cancer metabolism, as they will inevitably have systemic effects. For example, inhibition of mitochondrial complex I (CI), despite showing promising results as an anticancer approach, triggers TME-mediated survival mechanisms in subcutaneous osteosarcoma xenografts, a response that may vary according to whether the tumors are induced via subcutaneous injection or by intrabone orthotopic transplantation.

Lithium and Not Acetoacetate Influences the Growth of Cells Treated with Lithium Acetoacetate.

The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated the antiproliferative effects of lithium acetoacetate (LiAcAc) and sodium 3-hydroxybutyrate on cancer cells in vitro.

The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit?

The thriving field that constitutes cancer metabolism has unveiled some groundbreaking facts over the past two decades, at the heart of which is the TCA cycle and its intermediates. As such and besides its metabolic role, α-ketoglutarate was shown to withstand a wide range of physiological reactions from protection against oxidative stress, collagen and bone maintenance to development and immunity. Most importantly, it constitutes the rate-limiting substrate of 2-oxoglutarate-dependent dioxygenases family enzymes, which are involved in hypoxia sensing and in the shaping of cellular epigenetic landscape, two major drivers of oncogenic transformation.

Dansyl acetyl trehalose: a novel tool to investigate the cellular fate of trehalose.

A fluorescent derivative of trehalose with two dansyl groups (DAT) has been synthesized. It is characterised by a large Stokes shift, good permeability in human living cells and a well detectable fluorescent signal within the cells. Notably, in intestinal cells DAT is sequestered in vesicles induced by trehalose pre-treatment and colocalizes with lipid droplets.

Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses.

Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α).

The Paradigm of Respiratory Complex I.

Mitochondrial respiratory function is now recognized as a pivotal player in all the aspects of cancer biology, from tumorigenesis to aggressiveness and chemotherapy resistance. Among the enzymes that compose the respiratory chain, by contributing to energy production, redox equilibrium and oxidative stress, complex I assumes a central role. Complex I defects may arise from mutations in mitochondrial or nuclear DNA, in both structural genes or assembly factors, from alteration of the expression levels of its subunits, or from drug exposure.

Mutant MYO1F alters the mitochondrial network and induces tumor proliferation in thyroid cancer.

Familial aggregation is a significant risk factor for the development of thyroid cancer and familial non-medullary thyroid cancer (FNMTC) accounts for 5-7% of all NMTC. Whole exome sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.

Unravelling the Effects of the Mutation m.3571insC/MT-ND1 on Respiratory Complexes Structural Organization.

Mammalian respiratory complex I (CI) biogenesis requires both nuclear and mitochondria-encoded proteins and is mostly organized in respiratory supercomplexes. Among the CI proteins encoded by the mitochondrial DNA, NADH-ubiquinone oxidoreductase chain 1 (ND1) is a core subunit, evolutionary conserved from bacteria to mammals. Recently, ND1 has been recognized as a pivotal subunit in maintaining the structural and functional interaction among the hydrophilic and hydrophobic CI arms.

Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases.

There is growing evidence that the sequence variation of mitochondrial DNA (mtDNA), which clusters in population- and/or geographic-specific haplogroups, may result in functional effects that, in turn, become relevant in disease predisposition or protection, interaction with environmental factors and ultimately in modulating longevity. To unravel functional differences between mtDNA haplogroups we here employed transmitochondrial cytoplasmic hybrid cells (cybrids) grown in galactose medium, a culture condition that forces oxidative phosphorylation, and in the presence of rotenone, the classic inhibitor of respiratory Complex I. Under this experimental paradigm we assessed functional parameters such as cell viability and respiration, ATP synthesis, reactive oxygen species production and mtDNA copy number.

Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber's hereditary optic neuropathy.

We here report on the existence of Leber's hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband's fibroblasts into the cybrid cell model. Finally, all but one of these missense mtDNA variants cluster along the same predicted fourth E-channel deputed to proton translocation within the transmembrane domain of Complex I, involving the ND1, ND4L and ND6 subunits.