Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.

The machineries, regulation and cellular functions of mitochondrial calcium.

Endoplasmic Reticulum–Mitochondrial Contactology: Structure and Signaling Functions

Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.

Mitochondrial Function, Biology, and Role in Disease A Scientific Statement From the American Heart Association

The burden of cardiovascular and metabolic diseases worldwide is staggering. The emergence of systems approaches in biology promises new therapies, faster and cheaper diagnostics, and personalized medicine. However, a profound understanding of pathogenic mechanisms at the cellular and molecular levels remains a fundamental requirement for discovery and therapeutics. Animal models of human disease are cornerstones of drug discovery as they allow identification of novel pharmacological targets by linking gene function with pathogenesis. The zebrafish model has been used for decades to study development and pathophysiology. More than ever, the specific strengths of the zebrafish model make it a prime partner in an age of discovery transformed by big-data approaches to genomics and disease. Zebrafish share a largely conserved physiology and anatomy with mammals. They allow a wide range of genetic manipulations, including the latest genome engineering approaches. They can be bred and studied with remarkable speed, enabling a range of large-scale phenotypic screens. Finally, zebrafish demonstrate an impressive regenerative capacity scientists hope to unlock in humans. Here, we provide a comprehensive guide on applications of zebrafish to investigate cardiovascular and metabolic diseases. We delineate advantages and limitations of zebrafish models of human disease and summarize their most significant contributions to understanding disease progression to date.

Little Fish, Big Data: Zebrafish as a Model for Cardiovascular and Metabolic Disease

Intracellular Ca(2+) signaling and Ca(2+) microdomains in the control of cell survival, apoptosis and autophagy.

Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these findings demonstrate a critical modulatory role for VDAC2-dependent mitochondrial Ca(2+) uptake in the regulation of cardiac rhythmicity.

/pdf/mitochondrial-ca-2-uptake-by-the-voltage-dependent-anion-5bba7m290i.pdf

Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity.

Ethyl 2-(triphenylphosphoranylidne)propionate




Ethyl 2-methylbuta-2,3-dienoate




(E)-N-Benzylidene-4-methylbenzenesulfonamide




p-Tolunesulfonamide




Benzaldehyde




BF3.Et2O




Ethyl 6-phenyl-1-tosyl-1,2,5,6-tetrahydropyridene-3-carboxylate




Tri-n-butylphosphine





Keywords:

phosphine catalyst;
annulation;
tetrahydropyridines;
ethyl-1,2-methyl-2,3-butadienoate;
tosylaldimines;
mechanisms;
ethyl2-arylmethyl-2,3-butadienoates;
waste disposal;
safety

/pdf/phosphine-catalyzed-4-2-annulation-synthesis-of-ethyl-6-1i6h562mhi.pdf

Kui Lu

Papers

Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity.

Phosphine-catalyzed [4+2] annulation: synthesis of ethyl 6-phenyl-1-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate