Proteolytic regulation of mitochondrial magnesium channel MRS2 by m-AAA protease and prohibitin complex.

Mitochondrial membrane phospholipid cardiolipin is essential for the stability of several inner mitochondrial membrane protein complexes. We recently showed that the abundance of mitochondrial magnesium channel MRS2 is reduced in models of Barth syndrome, an X-linked genetic disorder caused by a remodeling defect in cardiolipin. However, the mechanism underlying the reduced abundance of MRS2 in cardiolipin-depleted mitochondria remained unknown.

Atomic vacancies of molybdenum disulfide nanoparticles stimulate mitochondrial biogenesis.

Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function. In this study, we designed molybdenum disulfide (MoS) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS nanosheets.

Mechanism of Action and Translational Potential of ()-Meclizine in Preemptive Prophylaxis Against Stroke.

Background: Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney.

FDX1 Is Required for the Biogenesis of Mitochondrial Cytochrome c Oxidase in Mammalian Cells.

Ferredoxins (FDXs) are evolutionarily conserved iron-sulfur (Fe-S) proteins that function as electron transfer proteins in diverse metabolic pathways. Mammalian mitochondria contain two ferredoxins, FDX1 and FDX2, which share a high degree of structural similarity but exhibit different functionalities. Previous studies have established the unique role of FDX2 in the biogenesis of Fe-S clusters; however, FDX1 seems to have multiple targets in vivo, some of which are only recently emerging.

Cardiolipin deficiency leads to the destabilization of mitochondrial magnesium channel MRS2 in Barth syndrome.

Barth syndrome (BTHS) is a debilitating X-linked cardio-skeletal myopathy caused by loss-of-function mutations in TAFAZZIN, a cardiolipin (CL)-remodeling enzyme required for the maintenance of normal levels of CL species in mitochondrial membranes. At present, how perturbations in CL abundance and composition lead to many debilitating clinical presentations in BTHS patients have not been fully elucidated. Inspired by our recent findings that CL is essential for optimal mitochondrial calcium uptake, we measured the levels of other biologically important metal ions in BTHS mitochondria and found that in addition to calcium, magnesium levels are significantly reduced.

Mitochondrial phospholipid metabolism in health and disease.

Studies of rare human genetic disorders of mitochondrial phospholipid metabolism have highlighted the crucial role that membrane phospholipids play in mitochondrial bioenergetics and human health. The phospholipid composition of mitochondrial membranes is highly conserved from yeast to humans, with each class of phospholipid performing a specific function in the assembly and activity of various mitochondrial membrane proteins, including the oxidative phosphorylation complexes. Recent studies have uncovered novel roles of cardiolipin and phosphatidylethanolamine, two crucial mitochondrial phospholipids, in organismal physiology.

Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer.

Dysregulation of cellular metabolism is a hallmark of breast cancer progression and is associated with metastasis and therapeutic resistance. Here, we show that the breast tumor suppressor gene SIM2 promotes mitochondrial oxidative phosphorylation (OXPHOS) using breast cancer cell line models. Mechanistically, we found that SIM2s functions not as a transcription factor but localizes to mitochondria and directly interacts with the mitochondrial respiratory chain (MRC) to facilitate functional supercomplex (SC) formation.

FDX1-dependent and independent mechanisms of elesclomol-mediated intracellular copper delivery.

Recent studies have uncovered the therapeutic potential of elesclomol (ES), a copper-ionophore, for copper deficiency disorders. However, we currently do not understand the mechanism by which copper brought into cells as ES-Cu(II) is released and delivered to cuproenzymes present in different subcellular compartments. Here, we have utilized a combination of genetic, biochemical, and cell-biological approaches to demonstrate that intracellular release of copper from ES occurs inside and outside of mitochondria.

Gastric Outlet Obstruction Secondary to Metastatic Breast Carcinoma 25 Years After Initial Diagnosis: A Mimic of Primary Gastric Carcinoma.

Although breast cancer is the most common form of cancer in women, metastasis to the stomach is incredibly rare. Gastric metastasis of breast cancer has been described in the literature, with an estimated median of 6 years from the initial diagnosis of primary breast cancer to metastasis and multiple instances greater than 10 years. In this case, a patient presented with gastric outlet obstruction in the setting of breast cancer metastasis to the pylorus 25 years after the original diagnosis.

Mitochondrial copper in human genetic disorders.

Copper is an essential micronutrient that serves as a cofactor for enzymes involved in diverse physiological processes, including mitochondrial energy generation. Copper enters cells through a dedicated copper transporter and is distributed to intracellular cuproenzymes by copper chaperones. Mitochondria are critical copper-utilizing organelles that harbor an essential cuproenzyme cytochrome c oxidase, which powers energy production.

Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models.

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death.

Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery.

Copper (Cu) and iron (Fe) are redox-active metals that serve as cofactors for many essential cellular enzymes. Disruption in the intracellular homeostasis of these metals results in debilitating and frequently fatal human disorders, such as Menkes disease and Friedreich's ataxia. Recently, we reported that an investigational anticancer drug, elesclomol (ES), can deliver Cu to critical mitochondrial cuproenzymes and has the potential to be repurposed for the treatment of Cu deficiency disorders.

A yeast suppressor screen links Coa4 to the mitochondrial copper delivery pathway for cytochrome c oxidase.

Cytochrome c oxidase (CcO) is a multimeric copper-containing enzyme of the mitochondrial respiratory chain that powers cellular energy production. The two core subunits of cytochrome c oxidase, Cox1 and Cox2, harbor the catalytic CuB and CuA sites, respectively. Biogenesis of each copper site occurs separately and requires multiple proteins that constitute the mitochondrial copper delivery pathway.

The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome Oxidase.

Copper is essential for the stability and activity of cytochrome oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the Cu and Cu sites, respectively. Biogenesis of these two copper sites of CcO occurs separately and requires a number of evolutionarily conserved proteins that form the mitochondrial copper delivery pathway.

Connecting copper and cancer: from transition metal signalling to metalloplasia.

Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient.

MCU-complex-mediated mitochondrial calcium signaling is impaired in Barth syndrome.

Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1.

Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.

Phosphatidylethanolamine (PE) is essential for mitochondrial respiration in yeast, Saccharomyces cerevisiae, whereas the most abundant mitochondrial phospholipid, phosphatidylcholine (PC), is largely dispensable. Surprisingly, choline (Cho), which is a biosynthetic precursor of PC, has been shown to rescue the respiratory growth of mitochondrial PE-deficient yeast; however, the mechanism underlying this rescue has remained unknown. Using a combination of yeast genetics, lipid biochemistry, and cell biological approaches, we uncover the mechanism by showing that Cho rescues mitochondrial respiration by partially replenishing mitochondrial PE levels in yeast cells lacking the mitochondrial PE-biosynthetic enzyme Psd1.

A genome-wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity.

Copper is essential for the activity and stability of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Loss-of-function mutations in genes required for copper transport to CcO result in fatal human disorders. Despite the fundamental importance of copper in mitochondrial and organismal physiology, systematic identification of genes that regulate mitochondrial copper homeostasis is lacking.

Molecular nature and physiological role of the mitochondrial calcium uniporter channel.

Calcium (Ca) signaling is critical for cell function and cell survival. Mitochondria play a major role in regulating the intracellular Ca concentration ([Ca]). Mitochondrial Ca uptake is an important determinant of cell fate and governs respiration, mitophagy/autophagy, and the mitochondrial pathway of apoptosis.

Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism.

Mitochondria house evolutionarily conserved pathways of carbon and nitrogen metabolism that drive cellular energy production. Mitochondrial bioenergetics is regulated by calcium uptake through the mitochondrial calcium uniporter (MCU), a multi-protein complex whose assembly in the inner mitochondrial membrane is facilitated by the scaffold factor MCUR1. Intriguingly, many fungi that lack MCU contain MCUR1 homologs, suggesting alternate functions.

An essential role for cardiolipin in the stability and function of the mitochondrial calcium uniporter.

Calcium uptake by the mitochondrial calcium uniporter coordinates cytosolic signaling events with mitochondrial bioenergetics. During the past decade all protein components of the mitochondrial calcium uniporter have been identified, including MCU, the pore-forming subunit. However, the specific lipid requirements, if any, for the function and formation of this channel complex are currently not known.

Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice.

Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria.