New & Noteworthy

Degradation of Mmr1 protein vital for mitochondrial dynamics

April 29, 2022

Regulating mitochondrial dynamics during cell division is crucial for maintaining homeostasis in eukaryotic cells. In budding yeast, proteins such as Myo2p and Mmr1p are essential to transport mitochondria into the growing bud, which post cell division, exists as an independent daughter cell. Improper inheritance and/or distribution of mitochondria can generate reactive oxygen species (ROS) toxicity in daughter cells.

An interesting new study by Obara K et al. in Nature Communications shows that degradation of Mmr1p is crucial in maintaining mitochondrial homeostasis in budding yeast. During cell division, Mmr1p bridges mitochondria and Myo1p and assists in its transportation to the bud via actin cables. Once the transportation is complete, kinases such as Ste20p and Cla4p phosphorylate Mmr1, leading to its recognition and poly-ubiquitination by E3 ligases, Dma1p/Dma2p. The proteasome degrades the poly-ubiquitinated and phosphorylated Mmr1p, and the mitochondria are released from Myo2p and distributed in the bud. Once released, Myo2p translocates to the bud neck.  

From Obara K et al., 2022

The study shows that in the absence of Dma1p/Dma2p, the transported mitochondria are not released from the actin-myosin machinery but in fact, become expanded or deformed and accumulate at the bud tip and then at the bud neck (due to translocation of Myo2p). Double mutants with altered mitochondrial morphology exhibit elevated respiratory activity and increased generation of ROS, rendering cells hypersensitive to oxidative stress

From Obara K et al., 2022

Additionally, the authors show that bud-localized kinases, Ste20p, and Cla4p phosphorylate (most probably) the serine residue at amino acid 414 of Mmr1p and regulate its degradation only after the mitochondria are transported to the growing bud, a crucial step in proper mitochondrial distribution.

Thus, the study highlights the importance of Mmr1p, Dma1p, and Dma2p in maintaining mitochondrial morphology and distribution required to sustain cell homeostasis in yeast cells.

Categories: Research Spotlight

Tags: cell division, cell homeostatis, mitochondrial inheritance, Saccharomyces cerevisiae

Polarity Linked to Lifespan in Mother Yeast Cells

April 01, 2022

In last week’s post, we discussed asymmetry in pH between mother and daughter cells. This week we’re continuing the theme of mother/daughter inheritance patterns with a study of asymmetrical mitochondrial inheritance. The underlying hope is to garner clues about aging and lifespan, since mother cells have reduced lifespan relative to their daughters.

Yeast cells are normally symmetrical, i.e. round. One of the first steps during cell growth is the breaking of symmetry to create poles, where one pole will become the bud tip and the other pole will become the mother cell tip. In a recent paper in iScience, Yang et al. describe how the mother cell tip is normally distal to the bud tip and that higher-functioning mitochondria localize to both poles. The mitochondrial F box protein Mfb1p was shown to be key for tethering mitochondria at the mother cell tip, which prevents every higher-functioning mitochondria from going to the bud. Mfb1p remains associated with the mother cell tip throughout the entire cycle, and is the only protein known to do this.

From Yang et al., 2022

Interestingly, Mfb1p is itself asymmetrically localized, where it associates with mitochondria in the mother cell but remains excluded from the daughter cell until just before cytokinesis.

To assess the link between aging and polarity, the authors labeled bud scars with dyes that distinguished between new and old scars. In highly polarized cells, new scars will form directly next to one another. They found polarized bud site selection in >97% of young cells, which was quickly reduced to 89% after 6–10 divisions and plateaued at ~70% for the oldest cells. Thus, aging as a factor of polarity was detectable early in lifespan and continued to decline to a fixed level. Likewise, the polarized localization of Mfb1p to mother cell tips also declined with age, where young cells showed Mfb1p tethered to mitochondria almost exclusively at the mother cell tips, but over time the localization dispersed throughout the mother cell. Interestingly, deletion of RSR1/BUD1 (required for polarized bud site selection) disrupted this polarized localization of Mfb1p within the mother, yet didn’t cause Mfb1p to go to the bud (i.e. cause loss of asymmetry). Thus, polarization and asymmetry could be separated in the bud1Δ mutant cells—and these cells also showed reduced lifespan. The same was seen in bud2Δ and bud5Δ cells.

Given that both bud1Δ and mfb1Δ cells had reduced lifespan, the authors asked whether the two mutations affected lifespan in the same way by examining the double mutant for additive effects. Seeing no additive effects, they concluded that BUD1 and MFB1 operate in the same pathway for controlling mitochondrial distribution and the associated effects on aging.

Whereas the study we highlighted last week did not find a link between aging and pH in yeast, Yang et al. show that mitochondrial localization and inheritance patterns have a clear relationship with replicative lifespan. The secrets of aging continue to invite study, and future results should be equally intriguing.  

Categories: Research Spotlight

Tags: mitochondria, mitochondrial inheritance, polarity in yeast, Saccharomyces cerevisiae, yeast inheritance, yeast model for aging