The mitochondrial proteome and human disease

Abstract

For nearly three decades, the sequence of the human mitochondrial genome (mtDNA) has provided a molecular framework for understanding maternally inherited diseases. However, the vast majority of human mitochondrial disorders are caused by nuclear genome defects, which is not surprising since the mtDNA encodes only 13 proteins. Advances in genomics, mass spectrometry, and computation have only recently made it possible to systematically identify the complement of over 1,000 proteins that comprise the mammalian mitochondrial proteome. Here, we review recent progress in characterizing the mitochondrial proteome and highlight insights into its complexity, tissue heterogeneity, evolutionary origins, and biochemical versatility. We then discuss how this proteome is being used to discover the genetic basis of respiratory chain disorders as well as to expand our definition of mitochondrial disease. Finally, we explore future prospects and challenges for using the mitochondrial proteome as a foundation for systems analysis of the organelle.

Figure 1

Tissue diversity of the mitochondrial proteome. (a) Estimate of mitochondrial abundance across tissues using cytochrome c as a proxy, reproduced with permission from Pagliarini et al. (). (b) Number of distinct proteins detected by tandem mass spectrometry (MS/MS) within 14 mouse tissues (). (c) Protein expression of protein complexes across tissues, where black indicates lack of detection and red indicates abundance levels if detected (). (d) Mitochondrial mRNA coexpression, shown as a pairwise correlation matrix based on GNF mouse tissue expression (), where red represents strong positive correlation. Prominent clusters of coexpressed genes are annotated based on their pathway or primary tissue of expression. Abbreviation: FA, fatty acid; OXPHOS, oxidative phosphorylation system

Figure 2

Evolutionary history of all 24,000 human protein-encoding genes (a) and of 1100 protein-encoding mitochondrial genes (b), based on sequence similarity to proteins in 500 fully sequenced species ().

Figure 3

Biological pathways underlying respiratory chain disease (RCD), adapted from Kirby et al. (). Bottom panel lists 92 protein-encoding genes that have been shown to cause RCD, including 79 genes encoded in the nucleus and 13 encoded by the mtDNA. Noted are genes associated with specific complexes (I--V) or iron/sulfur cluster biogenesis (Fe/S). Not listed are the 24 noncoding mtDNA genes that can also underlie RCD (2 rRNA and 22 tRNA genes). Abbreviation: OXPHOS, oxidative phosphorylation

Figure 4

Exploring the relationship between disease genes, biological pathways, and clinical features. Causal genes provide a link between clinical features and biological pathways (left), enabling the creation of multidimensional datasets (middle) that can be used to address biological queries (right). Examples are derived from the MitoPhenome database integrated with Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathways. Disease gene candidates, reported by Scharfe et al. are derived from known disease genes with similar phenotypic consequences as well as functionally related genes ().