Hallmarks of a new era in mitochondrial biochemistry

Abstract

Stemming from the pioneering studies of bioenergetics in the 1950s, 1960s, and 1970s, mitochondria have become ingrained in the collective psyche of scientists as the "powerhouses" of the cell. While this remains a worthy moniker, more recent efforts have revealed that these organelles are home to a vast array of metabolic and signaling processes and possess a proteomic landscape that is both highly varied and largely uncharted. As mitochondrial dysfunction is increasingly being implicated in a spectrum of human diseases, it is imperative that we construct a more complete framework of these organelles by systematically defining the functions of their component parts. Powerful new approaches in biochemistry and systems biology are helping to fill in the gaps.

Keywords: biochemistry; mitochondria; proteomics.

Figure 1.

The changing tides of mitochondrial research. To estimate the relative attention given to mitochondrial biology in each year from 1951 to 2012, we divided the number of PubMed entries containing “mitochondria” in the title or abstract or as a keyword by the total number of PubMed entries. The ratio for each year was normalized to that of 1951, which was set to 1.

Figure 2.

Model studies for identifying new functions for mitochondrial proteins. (A) Phylogenetic profiling leverages shared evolutionary history to highlight functionally related proteins. Pagliarini et al. (2008) used this approach to identify 19 MitoCarta proteins that shared the same evolutionary history as a subset of known CI subunits. These proteins include C8orf38, which harbors causative mutations in a CI deficiency. (B) Genetic interaction screens are another powerful way to associate proteins involved in shared complexes or pathways. Osman et al. (2009) used this approach to identify genes that, when knocked out on a phb1Δ background, caused a synthetic sick/synthetic lethal phenotype. Multiple such genes were found to be involved in lipid metabolism, including GEP4, which catalyzes a key step in CL biosynthesis. The bar graph, adapted by permission from Macmillan Publishers Ltd. from Osman et al. (2010) (© 2010), shows the accumulation of PGP, the GEP4 substrate, in gep4Δ yeast. (C) It has long been known that ER and mitochondria are somehow connected, but the proteins that help form these junctions remained elusive. Kornmann et al. (2009) identified the first components of the so-called ERMES complex using what they called a synthetic biology screen, in which they screened for mutants that could be complemented by a synthetic protein designed to artificially tether the two organelles. From Kornmann et al. (2009). Reprinted with permission from AAAS. (D) Perocchi et al. (2010) used an integrative computational strategy that included comparative physiology, evolutionary genomics, and mitochondrial proteomics information to prioritize candidates for the long-sought-after MCU. Based on decades of literature, the investigators predicted that components of the MCU would be localized to the mitochondrial IM, expressed in the majority of mammalian tissues, and have homologs in kinetoplastids but not in S. cerevisiae. This study validated MICU1 as a component of the MCU.

Figure 3.

Estimating the unannotated mammalian mitochondrial proteome. (A) Collectively, the human MitoCarta catalog and the orphan matrix mitochondrial proteins from Rhee et al (2013). comprise 1097 proteins. We estimate that 11%–36% of these proteins do not have clearly defined functions/biochemical activities. (B) The estimates in A were based on three approaches: (1) appearance of gene names in the title or abstract of PubMed citations, (2) association with an experimental evidence code in the GO database, and (3) manual inspection of the literature and various additional data sources. (C) Three-hundred-ninety-seven genes encoding mitochondrial proteins are associated with a human disease in either the GenCards or Online Mendelian Inheritance in Man (OMIM) databases. Twenty-nine of these genes also encode proteins of unknown function based on our manual inspection criteria.