Consequences of defective mitochondrial protein import: From targeting signals to pathology

Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.