- Open Access
Proteomic view of mitochondrial function
© BioMed Central Ltd 2008
- Published: 29 February 2008
Genomic and proteomic studies have identified hundreds of proteins from mitochondria. A recent study has added a functional twist to these systematic approaches and identified novel mitochondrial modifiers and regulators.
- Mitochondrial Protein
- Mitochondrial Morphology
- Mitochondrial Fusion
- Mitochondrial Network
- Multicellular Eukaryote
To carry out these functions, a mitochondrion is composed of hundreds of different proteins, most of which are encoded by genes in the nucleus. To better understand the complexity of mitochondrial functions we need to identify all the mitochondrial components and to unravel the cytoplasmic signaling pathways that regulate the organelle's activities. To these ends, various systematic approaches to mitochondrial protein identification have been undertaken in the past ten years. While most of these studies aimed at producing inventories of mitochondrial proteins, a recent study by Chen et al.  has specifically assayed the proteome of the fruit fly Drosophila melanogaster for proteins that are likely to be involved in the energy-generating functions of mitochondria and has identified several novel mitochondrial regulators.
The central role of mitochondria in both life and the death of the eukaryotic cell emerges not only from their biosynthetic functions but also from their crucial role in cellular signaling. In cooperation with the endoplasmic reticulum, mitochondria play an important role in the cellular homeostasis of Ca2+ . They also have a major role in triggering apoptosis, as several different pro-apoptotic signals are integrated and interpreted at the mitochondrial level. In response to these apoptotic signals, mitochondrial factors - the most prominent being cytochrome c and apoptosis-inducing factor (AIF) - are released to activate downstream signaling proteins and the caspases that execute apoptosis . In the course of these events, dramatic alterations in the mitochondrial network take place. These morphological changes are mediated by the same machineries that control mitochondrial morphology under normal conditions .
To fulfill all these functions, mitochondria have to maintain their unique protein composition, which is dynamic and adapts itself to the requirements of the organelle and the rest of the cell. The vast majority of mitochondrial proteins are encoded in the nucleus and synthesized as precursor proteins on cytosolic ribosomes. They are targeted to the mitochondria and become sorted to the correct sub-mitochondrial destination by an elaborate network of translocases and sorting machineries . Reminiscent of their endosymbiotic descent, mitochondria host their own DNA genome, which encodes only a few components of the respiratory-chain complexes (for example, 8 in Saccharomyces cerevisiae and 13 in human). Many more proteins are involved in the intra-organelle transcription and translation of this limited number of genes. Newly synthesized precursor proteins acquire their native conformation with the help of a dedicated set of mitochondrial chaperones . The organelle also harbors an independent quality-control system and misfolded proteins are degraded by mitochondrial proteases such as the AAA-proteases of the matrix and the intermembrane space and by the Lon-protease in the matrix .
Various systematic approaches for identifying mitochondrial components and associated signaling proteins have been developed. The proteomes of mitochondria from yeast [9–12], the filamentous fungus Neurospora crassa , mouse [14–16], human cells  and plants  have been systematically analyzed. Collectively, approximately 700 mitochondrial proteins have been identified in yeast and around 500 in rodent and human cells. Interestingly, plant and human mitochondria were found to harbor kinases and other regulatory proteins that are less abundant in yeast mitochondria. This observation is in accordance with the higher diversity of mitochondria in higher eukaryotes compared with the somewhat limited variability in the unicellular S. cerevisiae. In higher eukaryotes, each cell type may have distinct tasks for mitochondria, which are reflected by differing localizations and morphologies of the organelle in different cells, tissues and organs of the same organism. To address the diversity in the mitochondrial composition among different cell types, Mootha and coworkers  analyzed the mitochondrial proteomes from different mouse tissues. Surprisingly, the authors propose that about half of the 'complete' mitochondrial proteome is ubiquitously expressed, whereas the expression of the other half is tissue specific.
In the past couple of years the central role of mitochondria in cellular aging has become apparent. It is well established that mitochondrial DNA (mtDNA) accumulates mutations with aging, but a causal link between such mutations and the early onset of aging was shown only recently. An impressive example of this is the 'mutator mouse', in which an error-prone mitochondrial DNA polymerase leads to early onset of aging, and which shows a clear correlation between aging and increased mutation rate in the mitochondrial genome .
Defects in mitochondria in human cells often have devastating consequences for the cell and consequently for the whole human body. Many mitochondrial diseases, such as mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS, a cause of dementia), myoclonic epilepsy associated with ragged-red fibers (MERRF) and Leber's hereditary optic neuropathy (LHON), are caused by mutations in mtDNA. These mutations lead in most cases to dysfunction of the complexes involved in oxidative phosphorylation and thus to inefficient cellular respiration, with a resulting wide range of heterogeneous symptoms . Mutations in genes encoding components of mitochondrial import systems (Mohr-Tranebjaerg syndrome) and mitochondrial morphology (dominant optic atrophy, Charcot-Marie-Tooth neuropathy type 2A, Wolf-Hirschhorn syndrome) also lead to pathological disorders [24, 25]. Furthermore, mitochondria have recently been found to interact with many of the proteins specifically implicated in genetic forms of neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease .
The accumulation of data from different approaches and various organisms is helping us to get closer to a complete inventory of the mitochondrial proteome. However, despite this recent progress, our understanding of how mitochondria adapt their set of proteins to the requirements of the rest of the eukaryotic cell and how such cross-talk is regulated is only partial, and many loose ends have to be connected. Information on the precise suborganellar location of each mitochondrial protein and its individual function is still missing. This knowledge, together with analysis of the regulatory circuits inside and outside mitochondria, will be necessary to understand how this essential organelle plays its pivotal role in the life and death of eukaryotic cells.
We thank J Herrmann and L Scorrano for helpful comments. Our work is supported by grants from the Deutsche Forschungsgemeinschaft (SFB 446-A30 and RA 1028/2-1).
- Scheffler IE: A century of mitochondrial research: achievements and perspectives. Mitochondrion. 2001, 1: 3-31. 10.1016/S1567-7249(00)00002-7.PubMedView ArticleGoogle Scholar
- Chen J, Shi X, Padmanabhan R, Wang Q, Wu Z, Stevenson SC, Hild M, Garza D, Li H: Identification of novel modulators of mitochondrial function by a genome-wide RNAi screen in Drosophila melanogaster. Genome Res. 2008, 18: 123-136. 10.1101/gr.6940108.PubMedPubMed CentralView ArticleGoogle Scholar
- Romagnoli A, Aguiari P, De Stefani D, Leo S, Marchi S, Rimessi A, Zecchini E, Pinton P, Rizzuto R: Endoplasmic reticulum/mitochondria calcium cross-talk. Novartis Found Symp. 2007, 287: 122-139.PubMedView ArticleGoogle Scholar
- Keeble JA, Gilmore AP: Apoptosis commitment - translating survival signals into decisions on mitochondria. Cell Res. 2007, 17: 976-984. 10.1038/cr.2007.101.PubMedView ArticleGoogle Scholar
- Dimmer KS, Scorrano L: (De)constructing mitochondria: what for?. Physiology. 2006, 21: 233-241. 10.1152/physiol.00010.2006.PubMedView ArticleGoogle Scholar
- Neupert W, Herrmann JM: Translocation of proteins into mitochondria. Annu Rev Biochem. 2007, 76: 723-749. 10.1146/annurev.biochem.76.052705.163409.PubMedView ArticleGoogle Scholar
- Martinus RD, Ryan MT, Naylor DJ, Herd SM, Hoogenraad NJ, Hoj PB: Role of chaperones in the biogenesis and maintenance of the mitochondrion. FASEB J. 1995, 9: 371-378.PubMedGoogle Scholar
- Koppen M, Langer T: Protein degradation within mitochondria: versatile activities of AAA proteases and other peptidases. Crit Rev Biochem Mol Biol. 2007, 42: 221-242. 10.1080/10409230701380452.PubMedView ArticleGoogle Scholar
- Prokisch H, Scharfe C, Camp DG, Xiao W, David L, Andreoli C, Monroe ME, Moore RJ, Gritsenko MA, Kozany C, Hixson KK, Mottaz HM, Zischka H, Ueffing M, Herman ZS, Davis RW, Meitinger T, Oefner PJ, Smith RD, Steinmetz LM: Integrative analysis of the mitochondrial proteome in yeast. PLoS Biol. 2004, 2: 795-804. 10.1371/journal.pbio.0020160.View ArticleGoogle Scholar
- Zahedi RP, Sickmann A, Boehm AM, Winkler C, Zufall N, Schonfisch B, Guiard B, Pfanner N, Meisinger C: Proteomic analysis of the yeast mitochondrial outer membrane reveals accumulation of a subclass of preproteins. Mol Biol Cell. 2006, 17: 1436-1450. 10.1091/mbc.E05-08-0740.PubMedPubMed CentralView ArticleGoogle Scholar
- Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW, Weissman JS, O'Shea EK: Global analysis of protein localization in budding yeast. Nature. 2003, 425: 686-691. 10.1038/nature02026.PubMedView ArticleGoogle Scholar
- Kumar A, Agarwal S, Heyman JA, Matson S, Heidtman M, Piccirillo S, Umansky L, Drawid A, Jansen R, Liu Y, Cheung KH, Miller P, Gerstein M, Roeder GS, Snyder M: Subcellular localization of the yeast proteome. Genes Dev. 2002, 16: 707-719. 10.1101/gad.970902.PubMedPubMed CentralView ArticleGoogle Scholar
- Schmitt S, Prokisch H, Schlunck T, Camp DG, Ahting U, Waizenegger T, Scharfe C, Meitinger T, Imhof A, Neupert W, Oefner PJ, Rapaport D: Proteome analysis of mitochondrial outer membrane from Neurospora crassa. Proteomics. 2006, 6: 72-80. 10.1002/pmic.200402084.PubMedView ArticleGoogle Scholar
- Da Cruz S, Xenarios I, Langridge J, Vilbois F, Parone PA, Martinou JC: Proteomic analysis of the mouse liver mitochondrial inner membrane. J Biol Chem. 2003, 278: 41566-41571. 10.1074/jbc.M304940200.PubMedView ArticleGoogle Scholar
- Mootha VK, Bunkenborg J, Olsen JV, Hjerrild M, Wisniewski JR, Stahl E, Bolouri MS, Ray HN, Sihag S, Kamal M, Patterson N, Lander ES, Mann M: Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell. 2003, 115: 629-640. 10.1016/S0092-8674(03)00926-7.PubMedView ArticleGoogle Scholar
- Ozawa T, Sako Y, Sato M, Kitamura T, Umezawa Y: A genetic approach to identifying mitochondrial proteins. Nat Biotechnol. 2003, 21: 287-293. 10.1038/nbt791.PubMedView ArticleGoogle Scholar
- Gaucher SP, Taylor SW, Fahy E, Zhang B, Warnock DE, Ghosh SS, Gibson BW: Expanded coverage of the human heart mitochondrial proteome using multidimensional liquid chromatography coupled with tandem mass spectrometry. J Proteome Res. 2004, 3: 495-505. 10.1021/pr034102a.PubMedView ArticleGoogle Scholar
- Heazlewood JL, Tonti-Filippini JS, Gout AM, Day DA, Whelan J, Millar AH: Experimental analysis of the Arabidopsis mitochondrial proteome highlights signaling and regulatory components, provides assessment of targeting prediction programs, and indicates plant-specific mitochondrial proteins. Plant Cell. 2004, 16: 241-256. 10.1105/tpc.016055.PubMedPubMed CentralView ArticleGoogle Scholar
- Dimmer KS, Fritz S, Fuchs F, Messerschmitt M, Weinbach N, Neupert W, Westermann B: Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Mol Biol Cell. 2002, 13: 847-853. 10.1091/mbc.01-12-0588.PubMedPubMed CentralView ArticleGoogle Scholar
- Altmann K, Westermann B: Role of essential genes in mitochondrial morphogenesis in Saccharomyces cerevisiae. Mol Biol Cell. 2005, 16: 5410-5417. 10.1091/mbc.E05-07-0678.PubMedPubMed CentralView ArticleGoogle Scholar
- Ichishita R, Tanaka K, Sugiura Y, Sayano T, Mihara K, Oka T: An RNAi screen for mitochondrial proteins required to maintain the morphology of the organelle in C. elegans. J Biochem. 2008, doi:10.1093/jb/mvm245.Google Scholar
- Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom R, Törnell J, Jacobs HT, Larsson NG: Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004, 429: 417-423. 10.1038/nature02517.PubMedView ArticleGoogle Scholar
- Schapira AH: Mitochondrial disease. Lancet. 2006, 368: 70-82. 10.1016/S0140-6736(06)68970-8.PubMedView ArticleGoogle Scholar
- Schon EA, Manfredi G: Neuronal degeneration and mitochondrial dysfunction. J Clin Invest. 2003, 111: 303-312. 10.1172/JCI200317741.PubMedPubMed CentralView ArticleGoogle Scholar
- Chan DC: Mitochondria: dynamic organelles in disease, aging, and development. Cell. 2006, 125: 1241-1252. 10.1016/j.cell.2006.06.010.PubMedView ArticleGoogle Scholar
- Lin MT, Beal MF: Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006, 443: 787-795. 10.1038/nature05292.PubMedView ArticleGoogle Scholar