Proceedings of The Physiological Society

Mitochondria: Form and function (London, UK) (2017) Proc Physiol Soc 38, SA10

Research Symposium

Mitochondrial remodeling: Rearranging, recycling, and reprogramming

R. A. Gottlieb1

1. Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States.

Mitochondria, in keeping with their endosymbiont origins, are highly dynamic organelles, undergoing fusion and fission. Moreover, they are subject to cellular processes such as elimination via mitophagy or through ejection as exosomal particles. Mitochondrial mass is maintained at tissue-specific levels through biogenesis, a process that requires coordinated nuclear and mitochondrial gene expression and protein synthesis. Nuclear-encoded proteins are co-translationally imported from cytosol to mitochondria, a process depending on the complex protein import machinery that spans both mitochondrial outer and inner membranes. In response to stress such as ischemia/reperfusion injury, mitophagy is activated. In the heart, this process is Parkin-dependent but also involves optineurin, NDP52, and processing of Opa1. Homeostatic mechanisms are then initiated to restore mitochondrial mass to its original level, involving mtDNA replication and synthesis of both nuclear- and mitochondrial-encoded proteins. We are studying this process in the human heart and have found that during cardiac surgery involving cold cardioplegia there is evidence for both mitophagy and biogenesis. Moreover, we have preliminary evidence that this is regulated in part by miRNAs that suppress mito-biogenesis under normal conditions; depletion of these miRNAs from cytosolic polyribosomes occurs when mito-targeted protein translation is increased. Using Langendorff-perfused mouse hearts subjected to ischemia and reperfusion, we have identified an increase of mitochondria-targeted nuclear-encoded mRNAs associated with polysomes despite no change in total mRNA levels for these genes. Proteomic analysis of polysomes isolated by detergent extraction and sucrose gradient centrifugation revealed ribosomal proteins as well as numerous outer and inner membrane components of the mitochondrial protein import machinery, providing new evidence supporting co-translational protein import. Work is ongoing to identify the miRNAs that participate in this process in the mouse Langendorff model and to identify the newly-synthesized proteins.

Where applicable, experiments conform with Society ethical requirements