Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • Pimozide Introduction The failing heart has been considered

    2019-07-11

    Introduction The failing heart has been considered as an “energy-starved engine that has run out of fuel” [1,2]. For an adult heart, the turnover of ATP per day has been estimated to be 6 kg. The heart converts chemical energy stored in fatty acids, lactate, and glucose into the mechanical energy to pump blood through the body. Mitochondria are key to this energy conversion as they provide 95% of this energy through oxidative phosphorylation. The Krebs cycle produces the reducing equivalents NADH and FADH2, which are utilized by the respiratory chain and the F1/Fo ATP synthase to generate adenosine triphosphate (ATP). High energy demand results in increased levels of ADP, which accelerates ATP production at the F1Fo-ATP synthase and increases the activity of the respiratory chain. At the same time, production of reducing equivalents is increased by an upregulation of the Krebs cycle. Ca2+ plays a key role in activating several enzymes in the Krebs cycle. Ca2+ transmission from the cytosol into mitochondria is mediated by the mitochondrial calcium uniporter (MCU), which couples cytosolic elevation of Ca2+ induced by β-adrenergic stimuli with Ca2+ signaling in the mitochondrion. Besides their role in energy conversion, mitochondria have multiple functions in metabolism, such as the urea cycle, the metabolism of Pimozide and lipids, and the biogenesis of heme and iron‑sulfur clusters. Many mitochondrial functions are strongly associated to mitochondrial membranes. The outer membrane (OM) plays a role in connecting the mitochondrion to different organelles in the cell, including the sarco- or endoplasmic reticulum (SR/ER), the lysosome, and the plasma membrane [3,4]. These contacts are important for interorganellar communication and allow for exchanging lipids and small solutes between organelles [5]. The inner mitochondrial (IM) separates two compartments, the intermembrane space (IMS) from the matrix compartment. Invaginations of the IM form cristae structures, which harbor the respiratory chain and are crucial for the energy conversion by oxidative phosphorylation. The IM also forms the inner boundary membrane where the IM is in close opposition to the OM, which are the sites of protein import from the cytosol. Mitochondrial membranes are characterized by a unique phospholipid pool containing the dimeric phospholipid cardiolipin (CL), which is specific to mitochondrial membranes. CL contains two phosphatidylglyceride backbone molecules and therefore binds four fatty acids. Different fatty acids bound to all four positions give rise to a highly diversified CL pool in most mammalian tissues [6]. In contrast, the mammalian heart has a very defined CL species composition, with linoleic acid (18:2) being the predominant form for all four acyl chains bound to CL [7]. CL is involved in many essential functions linked to mitochondrial membranes including mitochondrial morphology, mitochondrial metabolism, and respiration. Accordingly, defects in the biosynthesis and remodeling of CL have been linked with severe disorders such as Sengers disease and Barth syndrome. Here we provide an overview of CL biosynthesis and the role of CL in various aspects of mitochondrial biology. We discuss the impact of changes in CL amount and species composition on cardiac physiology in inherited cardiomyopathies and acquired diseases, such as ischemia/reperfusion injury.
    CL biosynthesis, export and degradation
    Functions of CL in mitochondria
    Pathophysiology of CL deficiency
    Concluding remarks Mitochondria have evolved from bacterial progenitor via symbiosis with a host cell. A large number of these ancestral qualities are still preserved in mitochondria including the production of ATP by oxidative phosphorylation, the mitochondrial genome and the phospholipid CL. Mitochondria have adapted to take over many more functions in cellular metabolism, in autophagy, in apoptosis and in cellular signaling pathways. During evolution, also CL acquired new essential roles in many of the mitochondrial functions. We highlight a structural role in the mitochondrial respiratory chain, in protein translocases and in mitochondrial carrier proteins. Four acyl chains form a strongly hydrophobic anchor and two negatively charged phosphate groups provide the basis for tight interaction with protein complexes. Besides structural contributions, CL also actively contributes to enzymatic reactions. This has been shown for its role in proton transport in complexes III and V reaction cycle. A resonance-stabilized structure facilitates CL function as a “proton trap”. A series of studies also revealed an independent role of CL in signal transduction processes. Under mitochondrial stress conditions CL is actively transported to the OM and exposed to serve as a binding site in many cellular signaling events. During mitophagy, CL recruits essential regulators. Apoptotic signaling pathways require CL as a binding platform. The two phosphate groups in CL are destined to forms electrostatic interactions with positively charged residues in target proteins [197,198]. However a uniform binding site has not been identified, possibly reflecting different types of interactions serving multiple different functions [199].