Systems biology of the mitochondrion

The promise of the current era of biological research is to understand the integrated function of biological systems in order to predict and rationally manipulate their behavior, with the ultimate aim of improving human health. In a nutshell, “systems biology” attempts to realize this promise by measuring and mapping biological interactions within cells, tissues, organs, and organ systems, and predicting how integrated systems made up of many interacting components behave. Readers of the American Journal of Physiology may wish to point out that by such a definition, the term “systems biology” is essentially a synonym for “physiology.” While we would not argue with that assessment, we suggest that the increasing attention being paid to the endeavor is at least in part due to the injection of a new term, and associated new techniques and technologies, into the well-established field of integrative physiology. It has been argued that this increase in attention places the discipline of physiology in a position where it will either be “superseded…by systems biology” or will enjoy a renaissance as it leads the way in research in this area (22). We take the leading-edge research performed in physiology departments worldwide as evidence supporting the latter scenario.

Examples of such leading work are reported in this issue and in upcoming issues of AJP-Cell Physiology, which presents reviews, original reports, and perspectives articles that were received in response to a call for papers on the Systems Biology of the Mitochondrion—that is, the internal workings of the mitochondrion in terms of structural, biochemical, and electrophysiological processes and external interactions of mitochondria with processes occurring at the cell, tissue, and organ levels in health and disease. With this broad theme, the reviews and reports collected here partially cover state-of-the-art knowledge and technology regarding the systems function of mitochondria. In addition to the papers that use techniques typically associated with the systems biology, strong papers on mitochondrial physiology with interesting new findings or giving an overview of aspects of mitochondrial physiology were incorporated under this call. In addition, a number of articles (that at the time of press for this issue were working through various stages of the review and production process) will be published in forthcoming issues of the Journal under the heading of this call.

As is clear from the diverse foci of the papers found in this issue, mitochondria are involved in a great number of important physiological and pathophysiological processes. Certainly as the cellular organelle primarily responsible for transducing free energy from primary substrates into the ATP potential that drives the majority of energy-consuming processes in a cell, the mitochondrion plays a central role in most, if not all, intracellular events in eukaryotes. In addition, mitochondria play key roles in the scavenging and production of reactive oxygen species (ROS), and polymorphisms in mitochondrial genes have been linked to a number of conditions including diabetes, Parkinson disease, and certain cancers. Thus, as demonstrated in the articles highlighted here, systems research into mitochondrial function can have and is having impact on how we understand and treat a number of clinically important conditions.

Overview of Papers in This Call for Papers

Several papers in this call focus on computational tools and demonstrate how these tools are applied to research on mitochondrial function. Vo and Palsson (23) discuss how modern approaches are being applied to reveal the systems-level operation of this organelle. In their view (a view which is emerging as broad consensus), computational modeling plays a central role in research in biological systems. Balaban (2) provides powerful motivation for the endeavor in addressing the question: Why make models of mitochondrial function? In systems biology, one function of computational models is to serve as precise quantitative hypotheses that are challenged by comparison to experimental data. For example, Wu et al. (24) present the first mass- and charge-balanced computational model of in vivo oxidative phosphorylation in muscle. This model proposes that phosphate energy metabolite concentrations in oxidative metabolism are controlled primarily by feedback of substrate (ADP and inorganic phosphate) concentrations to the mitochondria. The favorable comparison of the model predictions of Wu et al. (24) to experimental data means that the hypothesis (the model) is not disproved. However, this failure to disprove does not rule out the possibility that other control mechanisms are present. An alternative hypothesis is provided by Liguzinksi and Korzeniewski (19), who present metabolic control analysis of a theoretical model that assumes that all NADH-producing and respiratory chain enzymes are activated in a parallel fashion coordinated with the changing ATP demands of the skeletal muscle cell. While mathematical models by Wu et al. (24) and Liguzinksi and Korzeniewski (19) deal with the short-term adaptation of oxidative phosphorylation, Devin and Rigoulet (10) review experimental data and mechanisms involved in long-term adaptation to changes in energy demand, using long-term adaptation in yeast, skeletal muscle, and C6 glioma cells as examples.

As models increase in sophistication and accuracy, and ability to computationally mimic the function of mitochondria in vivo improves, computer simulation will play an increasingly fundamental role in sorting out the complex integrated functions of the mitochondrion. In addition, computational techniques are essential in managing large-scale data that arise from proteomic and genomic research. Gabaldón (13) reviews the bioinformatics technologies developed to identify and characterize the function of mitochondrial proteins and discusses how functional predictions from such technologies have guided important experimental investigations.

While a simple view of the mitochondrion may be of an organelle with the single-minded function of synthesizing ATP, characterizing the functional diversity of mitochondria in different species and tissue types is an intriguing and important area of current research. From morphological, molecular, and biochemical observations of mitochondria from skeletal muscle, heart, liver, kidney, and brain, Benard et al. (4) classify mitochondria from these tissues into three functional classes: that of skeletal and cardiac muscle, that of brain, and that of liver and kidney. The intracellular three-dimensional arrangement of mitochondria in heart muscle cells from two species (rat and rainbow trout) was analyzed by Birkedal et al. (5). It is observed that some energetic properties of cardiac mitochondria from trout and rat are different and that the intracellular arrangement of cardiac mitochondria in different species vary from highly ordered (in rat) to almost random (in trout) (5). The quantitative description of three-dimensional arrangement of mitochondria given by Birkedal et al. (5) can be used in the mathematical models of intracellular energy fluxes, diffusion of oxygen, and interactions between mitochondria in the cells. The studies of Johnson et al. (16), which quantify and compare the mitochondrial proteomes from liver and heart, suggest a tremendous variability in the biochemical operation of mitochondria from different tissues.

While the mitochondrion's genome codes for only a small fraction of its proteome, variations in mitochondrial DNA (mtDNA) may significantly affect whole-organism physiology. A comprehensive review of studies on mtDNA performed during the last two decades is given by Khan et al. (18). In this review, the description of methods used in the studies of mtDNA is given together with the outline of prospects for the future mtDNA gene therapy. In their original article, Schlick et al. (21) present whole-genome sequences of mitochondria from 10 inbred rat strains and 2 wild rat strains. These sequences provide the basis for studying the impact of the mitochondrial genome in various rat models of human disease.

Mitochondrial function in pathophysiological conditions and diseases is a subject of several papers. Processes occurring in mitochondria during ischemia and reperfusion are reviewed by Chen et al. (8). They review the experimental data indicating that inhibition of mitochondrial electron transport or partial uncoupling of respiration during and immediately after an episode of ischemia can reduce the extent of mitochondrial injury. The role of alterations in cardiolipin (a phospholipid localized in the inner mitochondrial membrane that provides structural and functional support to several proteins and facilitates interactions between different proteins in mitochondria) in pathological conditions is a subject of review by Chicco and Sparagna (9). Modulation of mitochondrial energetics by influx of potassium through a mitochondrial calcium-sensitive potassium channel is studied by Heinen et al. (15). In this paper, the influence of the activation of this channel on mitochondrial membrane potential, respiration, and ROS production was analyzed to assess the role of this channel in protection against ischemia and reperfusion damage. Gerber et al. (14) present evidence of a previously unidentified long-chain fatty acid export system and investigate the role of this transporter in a diabetic rat model. They show that palmitate is generated and released from isolated rat cardiac mitochondria when palmitoyl carnitine is added. The amount released increases in mitochondria from streptozotocin-induced diabetic rat hearts (14). By measuring simultaneously oxygen concentration, extracellular acidification, and ATP concentration, the bioenergetic response of two human cancer cell lines to pharmacological modulators of cellular metabolism was analyzed by Wu et al. (25).

Diseases tied to mitochondrial malfunction include single-protein deficiencies, such as deficiencies in complex I and other respiratory enzymes. Wu et al. (24) predict the functional consequences of complex I and ANT (adenine nucleotide translocase) deficiencies on muscle energy metabolism. The review by Brière et al. (6) provides an overview of a number of diseases, including the formation of a variety of types of tumors, that are associated with deficiencies in tricarboxylic acid cycle enzyme activities. Dirks and Jones (11) give an overview of a limited data available on statin-induced apoptosis in muscle. The roles of aging mitochondria and failure of mitochondrial energetics, in particular, during development of Alzheimer disease have been reviewed by Parihar and Brewer (20).

Several papers address questions of how calcium ion concentration regulates and is regulated by mitochondrial function in both physiological and pathophysiological settings. Camello-Almaraz et al. (7) review data on the interplay between Ca²⁺ signaling and mitochondrial ROS generation, specifically reviewing evidence that mitochondrial-derived ROS plays a role in physiological regulation of the release of Ca²⁺ from intracellular stores in a variety of cell types. The study by Arrington et al. (1) demonstrates that calpain-10, a calcium-activated protease, is active in mitochondria and plays a functional role in calcium-activated permeability transition and complex I inhibition. Thus this study identifies a likely key player in apoptotic and other pathways tied to Ca²⁺ accumulation in mitochondria. Beltran-Parrazal et al. (3) investigated the effects of intracellular calcium on the intracellular trafficking of mitochondria in cortical neurons and showed that mitochondrial movement within axons and dendrites does not depend on intracellular Ca²⁺ signaling.

Fluxes of ions, including cations such as potassium ion, affect the osmolarity of the mitochondrial matrix and influence mitochondrial volume. The review by Kaasik et al. (17) describes the role of potassium in mitochondrial volume regulation and gives a short overview of phases of mitochondrial swelling and possible effects of the swelling on cell function.

Focusing at the molecular and genetic level, Fontanesi et al. (12) reviews current knowledge regarding the assembly of the cytochrome c oxidase complex, a coordinated process involving transcription of several genes from both the mitochondrial and nuclear genomes. This review also discusses models for the coordination of the respiratory chain, including the concept of supercomplexes of different respiratory chain enzymes being physically and functionally coupled in the mitochondrial inner membrane. Indeed, this supercomplex hypothesis is supported by data of Benard et al. (4) on the preserved stoichiometry of certain respiratory chain complexes in different tissue types.

Future Papers Published Under This Call for Papers

After several months of soliciting, editing, and reviewing papers under this call for papers, we found ourselves in the perhaps inevitable situation of having many accepted papers ready for publication and many still going through various stages of the review process. Rather than unnecessarily delaying the publication of accepted papers, it was decided to begin publications under this call in the December 2006 issue of the Journal. We anticipate a significant number of papers published under this call to appear in the January 2007 issue and to continue to appear throughout the year.