Estrutura e função dos complexos de proteína da membrana mitocondrial

quarta-feira, dezembro 23, 2015

Structure and function of mitochondrial membrane protein complexes

Werner Kühlbrandt Email author

BMC Biology201513:89

© Kühlbrandt. 2015

Published: 29 October 2015

Fig. 2 - Membrane protein complexes of the respiratory chain.

Abstract




Biological energy conversion in mitochondria is carried out by the membrane protein complexes of the respiratory chain and the mitochondrial ATP synthase in the inner membrane cristae. Recent advances in electron cryomicroscopy have made possible new insights into the structural and functional arrangement of these complexes in the membrane, and how they change with age. This review places these advances in the context of what is already known, and discusses the fundamental questions that remain open but can now be approached.

Mitochondria are the powerhouses of the cell. In all eukaryotes that do not depend on photosynthesis, the mitochondria are the main source of adenosine triphosphate (ATP), the energy-rich compound that drives fundamental cell functions. These functions include force generation (for example, in muscle contraction and cell division), the biosynthesis, folding and degradation of proteins, and the generation and maintenance of membrane potentials. ATP is produced on a massive scale in the human body, amounting to 50 kg per day in a healthy adult, but considerably more in a long-distance runner. ATP is generated by the mitochondrial ATP synthase from ADP and phosphate ions. These are the products of ATP hydrolysis at the sites where energy is needed in the cell. Apart from cellular respiration and ATP synthesis, mitochondria have numerous other essential functions, including the production of NADH and GTP in the citric acid cycle, the biosynthesis of amino acids, heme groups and iron-sulfur clusters or the synthesis of phospholipids for membrane biogenesis. They also act in calcium signaling [1], stress responses [2] and generally as cellular signaling hubs [3]. Not surprisingly, mitochondria play a fundamental role in human health. Mitochondrial dysfunction is the cause of severe, often maternally inherited diseases. Moreover, mitochondria are deeply implicated in apoptosis and ageing [4].

In many respects, mitochondria resemble α-proteobacteria, from which they are thought to have originated by endocytosis some 1.6 billion years ago. The most striking evidence of this evolutionary relationship is the close homology of bacterial and mitochondrial respiratory chain complexes. Mitochondria have their own genetic system, which uses a distinct DNA code that differs both from that of their bacterial ancestors and their eukaryotic hosts [5]. They have their own protein translation machinery, complete with ribosomes, tRNAs and associated protein factors that more or less resemble those of their bacterial ancestors. Very recently, the first high-resolution structure of a mitochondrial ribosome, determined by single-particle electron cryomicroscopy (cryo-EM), has revealed a fascinating patchwork of similarities to and differences from bacterial ribosomes [6]. Nevertheless, mitochondria make surprisingly little use of their specialized protein production machinery. In the course of evolution they have transferred up to 99 % of their genes to the nucleus. Today, the vast majority of mitochondrial proteins are produced in the cytoplasm and imported into the organelle by an elaborate set of protein translocases [7]. In humans, only 13 mitochondrial proteins are organelle-encoded, all of them central, hydrophobic subunits of respiratory chain complexes or of the ATP synthase.

Mitochondria are highly dynamic [8]. In the cell, they form a tubular network that constantly changes by division and fusion (Additional file 1). Both processes are accomplished by multi-component molecular machineries that include a number of dynamin-related GTPases [9, 10]. When mitochondria are isolated from cells, the network breaks up into fragments that spontaneously reseal. Isolated mitochondria are fully competent for respiration and ATP synthesis [11]. They maintain their membrane composition, organization and membrane potential, as well as the ability to fuse [12] and to import proteins [7]. We owe much of what we know about mitochondria and how they work at the molecular level to in vitro studies with isolated mitochondria, or even mitochondrial membrane fractions, which still carry out oxidative phosphorylation and ATP synthesis [13].

Mitochondria can be seen in the light microscope, but their detailed internal structure is only revealed by electron microscopy. In the 1990s, the structure of mitochondria was investigated by electron tomography of thin plastic sections [14]. While this yielded striking three-dimensional (3D) images of their internal membrane system, molecular detail was lost due to chemical fixation, dehydration and heavy-metal staining. Cryo-EM of unfixed, unstained organelles is now revealing the architecture of mitochondrial membranes and their macromolecular components at increasing levels of detail. Single-particle cryo-EM of isolated, detergent-solubilized membrane protein complexes reaches near-atomic resolution [15, 16]. Electron cryo-tomography (cryo-ET) of intact isolated mitochondria or mitochondrial membranes is resolving their macromolecular components in situ [17], and averaging of tomographic volumes can attain sub-nanometer resolution [18].

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