Mitochondrial quality control

Our lab’s long-term goal is to understand how mitochondria maintain the homeostasis of its proteome and genome. Known as the “powerhouse of the cell”, mitochondria are best known for their ability to make ATP. However, recent studies have revealed that mitochondria are multi-functional organelles involved in many other cellular pathways including protein homeostasis, apoptosis and stress response. Suffice to say, the health of the cell is closely linked to the health of the mitochondria, as dysfunction of mitochondria underlies many human diseases including neurological diseases and muscle diseases. So what controls the health of mitochondria? Our lab aims at approaching this question from two angles: how do mitochondria maintain their protein homeostasis, and how do mitochondria maintain their genomic stability?

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Protein quality control on the outer mitochondrial membrane

About one-third of the entire cellular proteome are membrane proteins. Upon synthesis, they are sorted to their target organelles. Cells use multiple proteins to ensure this sorting process happens faithfully and efficiently. However, the targeting reactions are not foolproof and some membrane proteins still end up on the wrong organelle due to targeting mistakes. To correct these targeting mistakes, cells use various machineries to actively look for mistargeted proteins and help remove them from the wrong organellar membrane. Recently, it was shown that an outer mitochondrial membrane (OMM) protein Msp1 (in yeast; ATAD1 in humans) is able to selectively recognize mistargeted membrane proteins on the OMM and physcially pull them out of the membrane. The extracted membrane proteins are then degraded or sent back to their target organelle. By doing so, Msp1/ATAD1 ensures the proper localization of membrane proteins and protects mitochondria from damage caused by the accumulation of mistargeted membrane proteins. ATAD1 deletion causes death in mice and multiple mutations in the human ATAD1 gene cause neurological disorders, highlighting its physiological importance (Msp1/ATAD1 review).

Previously, we determined the cryo-EM structures of Msp1 and ATAD1 and showed that it follows the conserved mechanism of AAA unfoldases, which assembles into a homohexamer and traps the substrate in the central pore. There, Msp1/ATAD1 uses multiple aromatic amino acids to firmly grid the substrate and to linearize and extract the it from the membrane (Msp1 paper; ATAD1 paper).