Selective sorting and destruction of mitochondrial membrane proteins in aged yeast

  • Hughes A
  • Hughes C
  • Henderson K
  • et al.
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Abstract

Mitochondrial dysfunction is a hallmark of aging, and underlies the development of many diseases. Cells maintain mitochondrial homeostasis through a number of pathways that remodel the mitochondrial proteome or alter mitochondrial content during times of stress or metabolic adaptation. Here, using yeast as a model system, we identify a new mitochondrial degradation system that remodels the mitochondrial proteome of aged cells. Unlike many common mitochondrial degradation pathways, this system selectively removes a subset of membrane proteins from the mitochondrial inner and outer membranes, while leaving the remainder of the organelle intact. Selective removal of preexisting proteins is achieved by sorting into a mitochondrial-derived compartment, or MDC, followed by release through mitochondrial fission and elimination by autophagy. Formation of MDCs requires the import receptors Tom70/71, and failure to form these structures exacerbates preexisting mitochondrial dysfunction, suggesting that the MDC pathway provides protection to mitochondria in times of stress.Our cells contain compartments called mitochondria, which provide energy and serve as a home for many metabolic pathways that are critical for life. Changes in mitochondrial activity can contribute to aging and to the development of several age-associated diseases. However, our cells contain systems that detect changes in the performance of mitochondria and can act to re-establish a healthy state. These systems respond to stress or changes in metabolism by degrading particular proteins in the mitochondria. This enables damaged or unwanted proteins to be replaced with new proteins, but it is not clear how these mitochondrial defense systems work to keep mitochondria healthy as an organism ages.Budding yeast is a good model in which to study the aging process because the performance of this yeast’s mitochondria change in a characteristic way as the yeast ages. Previous studies have shown that these changes are caused by alterations in another cell structure called the lysosome, which can store nutrients and is where many proteins are degraded.Here, Hughes et al. used yeast cells to investigate how mitochondrial defense systems operate during aging. The experiments reveal an entirely new mitochondrial protein degradation system that helps to keep the mitochondria healthy as the yeast cells age. This process is rapidly triggered by changes in lysosome activity and results in certain proteins in each mitochondrion being sorted into a small compartment made from a part of the mitochondrion. This compartment is released from the mitochondrion and then travels to the lysosome where the proteins are destroyed. Inhibiting the formation of these compartments results in mitochondria being more sensitive to cellular stress.The next steps following on from this work are to find out exactly what role this mitochondrial defense pathway plays in cells and why it targets only a small set of all the proteins found in mitochondria.

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Hughes, A. L., Hughes, C. E., Henderson, K. A., Yazvenko, N., & Gottschling, D. E. (2016). Selective sorting and destruction of mitochondrial membrane proteins in aged yeast. ELife, 5. https://doi.org/10.7554/elife.13943

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