Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import

Abstract

Mitochondrial disease represents a collection of rare genetic disorders caused by mitochondrial dysfunction. These disorders can be quite complex and heterogeneous, and it is recognized that mitochondrial disease can affect any tissue at any age. The reasons for this variability are not well understood. In this review, we develop and expand a subset of mitochondrial diseases including predominantly skeletal phenotypes. Understanding how impairment ofdiverse mitochondrial functions leads to a skeletal phenotype will help diagnose and treat patients with mitochondrial disease and provide additional insight into the growing list of human pathologies associated with mitochondrial dysfunction. The underlying disease genes encode factors involved in various aspects of mitochondrial protein homeostasis, including proteases and chaperones, mitochondrial protein import machinery, mediators of inner mitochondrial membrane lipid homeostasis, and aminoacylation of mitochondrial tRNAs required for translation. We further discuss a complex of frequently associated phenotypes (short stature, cataracts, and cardiomyopathy) potentially explained by alterations to steroidogenesis, a process regulated by mitochondria. Together, these observations provide novel insight into the consequences of impaired mitochondrial protein homeostasis.

Keywords: mitochondrial disease; protein homeostasis; protein import; skeletal abnormality.

Figure 1

Diagram of mitochondrial protein import pathways. Mitochondrial proteins are imported and targeted to their final destinations through a variety of interrelated pathways starting with the TOM (translocase of outer membrane) complex. Most proteins destined for the OMM (outer mitochondrial membrane) are inserted via the MIM (mitochondrial import machinery) (teal), with β-barrel proteins inserted via the SAM (sorting and assembly machinery) complex (green). Cysteine-rich proteins in the IMS (inner membrane space) are refolded via the MIA (mitochondrial import and assembly) pathway (blue). Proteins containing an MTS (mitochondrial targeting sequence) that are destined for the matrix or IMM (inner mitochondrial membrane) are transferred to the TIM23 complex and the MTS is removed (red). Finally, multi-spanning IMM proteins, such as the SLC family of carrier proteins, are inserted via the TIM22 complex (purple).

Figure 2

Model unifying the genes implicated in mitochondrial skeletal disorders to mitochondrial protein homeostasis. Proteases and chaperones mediate mitochondrial protein import and turnover of dysfunctional proteins. Impaired mitochondrial protein homeostasis inhibits mitochondrial protein import. IMM (inner mitochondrial membrane) lipid composition can impact proteases embedded in the IMM and is predicted to also impair mitochondrial protein import. Mitochondrial translation, which depends on tRNA aminoacylation, is essential for insertion of mtDNA-encoded proteins into the IMM, and is predicted to impact IMM proteases and/or mitochondrial protein import.