The exceptional longevity of the naked mole‐rat may be explained by mitochondrial antioxidant defenses

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12916

Daniel Munro, Cécile Baldy, Matthew E. Pamenter, Jason R. Treberg

TWO THEORIES OF AGEING

The oxidative damage theory of ageing postulates that  a slow and steady accumulation of oxidative damage to macromolecules, which increases with age, causes the decline of physiologic functions. The oxidative damage is caused by reactive oxygen species (ROS) of mitochondrial origin.

The mitochondrial oxidative stress hypothesis states that ageing is primarily driven by loss of mitochondrial function with time, caused by oxidative stress. This theory stems from the fact that ROS are mostly released inside mitochondria, therefore directly exposing them to damage.

THE PRESENT STUDY

Naked mole-rat (NMR) can live >30 years in lab conditions, with a very long healthy lifespan, in comparison to <4 years for mice. Studies have shown that NMRs are subject to extensive oxidative damage (evidence found in liver cells) and high ROS productions, as much as mice. Therefore, their longevity has been widely used to contradict the oxidative damage theory of ageing. The mitochondrial oxidative stress hypothesis cannot explain these observations.

The authors, writing in Aging Cell, showed that NMRs mitochondria are much more efficient than mice's in consuming ROS. They also find evidence that skeletal muscle and heart mitochondria of mice and NMRs produce similar quantities of ROS.  Therefore, the authors conclude that the marked difference in longevity between the two species is to be attributed to the much greater capacity of NMRs mitochondria to clean ROS.

This finding supports the mitochondrial oxidative stress hypothesis, without positing that NMRs mitochondria produce less ROS. Further research could tell whether other long-lived species share this greater mitochondrial detoxifying capacity.

Mechanisms of organelle biogenesis govern stochastic fluctuations in organelle abundance

Shankar Mukherji, Erin K O'Shea

https://elifesciences.org/articles/02678

• Modelled the dynamics of organelle biogenesis, finding that fluctuations in organelle abundance depend strongly on the specific mechanisms that influence organelle number
• Model predicts the experimentally measured size of the Golgi apparatus and vacuole abundance fluctuations
• Work provides a general framework for exploring stochastic organelle biogenesis

Excessive Cell Growth Causes Cytoplasm Dilution And Contributes to Senescence

https://www.sciencedirect.com/science/article/pii/S0092867419300510

Gabriel E. Neurohr, Rachel L. Terry, Jette Lengefeld, Megan Bonney, Gregory P. Brittingham, Fabien Moretto, Teemu P. Miettinen, Laura Pontano Vaites, Luis M. Soares, Joao A. Paulo, J. Wade Harper, Stephen Buratowski, Scott Manalis, Folkert J. van Werven, Liam J. Holt, Angelika Amon

• Cells of a particular type tend to display a relatively narrow range of cell sizes (relative to the orders-of-magnitude difference in cell size between cells of different types). 
• When cell cycle is blocked in budding yeast, cells continue to grow. The authors were able to reversibly arrest the cell cycle by perturbing a particular gene (CDC28), providing them with a x12-fold variation in cell volume. Note that denying these cells with glucose, or applying cyclohexamide, prevented the mutants from growing large.
• When allowed to re-enter the cell cycle, larger cells proliferated more slowly, and delays cell cycle progression.
• The authors observed that cell cycle regulators are produced at a lower rate in oversized cells (although the pool-size was comparable to normal cells).
• When cells exceeded ~200 fL, cellular growth shifted from exponential to linear
• In the linear growth regime, cell volume increased faster than total RNA and protein, suggesting dilution of cellular macro-molecules. Direct measurement of cellular density showed a 36% reduction in total cell density, largely explained by reductions in protein and RNA mass.
•  Transcriptome and proteome analysis suggested that general transcription and translation machineries becomes limiting in large cells.
• Using nocodazole to generate diploid cells, large diploid cells grew faster than large haploid cells, and also progressed faster through the cell cycle. The authors therefore suggest that the nDNA:(cytoplasmic volume) ratio is what limits cell growth in oversized cells.
• The authors found that the majority of old yeast cells (>16 cell divisions) were >200 fL and display many of the phenotypes of oversized cells. 
• Excessive increase in cell size was sufficient to reduce lifespan
• The authors tested many of these observations in human fibroblasts.

Thoughts
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• Some of the findings in here, especially relating to cellular growth rates, remind me of this
• Quantifying single-cell mtDNA copy number in this system would be extremely interesting! 

Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows

Thorsten B. Blum, Alexander Hahn, Thomas Meier, Karen M. Davies, and Werner Kühlbrandt

 

• ATP synthase is known to form dimers which form rows along curved ridges of mitochondrial cristae
• It has been suggested previously through computer simulation that these rows of ATP synthase cause local curvature
• This study shows experimentally, for the first time, that ATP synthase dimers spontaneously assemble into rows, and that these rows bend the membrane.
• The authors suggest that assembly of ATP synthase dimers into rows is likely the first step in the formation of cristae

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

https://doi.org/10.1016/j.cmet.2018.10.014

Bajzikova M, Kovarova J, Coelho AR, Boukalova S, Oh S, Rohlenova K, Svec D, Hubackova S, Endaya B, Judasova K, Bezawork-Geleta A, Kluckova K, Chatre L, Zobalova R, Novakova A, Vanova K, Ezrova Z, Maghzal GJ, Magalhaes Novais S, Olsinova M, Krobova L, An YJ, Davidova E, Nahacka Z, Sobol M, Cunha-Oliveira T, Sandoval-Acuña C, Strnad H, Zhang T, Huynh T, Serafim TL, Hozak P, Sardao VA, Koopman WJH, Ricchetti M, Oliveira PJ, Kolar F, Kubista M, Truksa J, Dvorakova-Hortova K, Pacak K, Gurlich R, Stocker R, Zhou Y, Berridge MV, Park S, Dong L, Rohlena J, Neuzil J.

• The authors graft cancer cells lacking mtDNA (ρ⁰) onto mice, and show horizontal transfer of mtDNA into the cancer cells after a lag period. After the transfer of mtDNA, a tumour subsequently develops. 
• The authors show that OXPHOS-derived ATP is not essential for tumorigenesis 
• Pyrimidine biosynthesis is dependent on respiration, and is required for cell-cycle progression

Mitochondrial complex III is essential for suppressive function of regulatory T cells

https://doi.org/10.1038/s41586-018-0846-z

Samuel E. Weinberg, Benjamin D. Singer, Elizabeth M. Steinert, Carlos A. Martinez, Manan M. Mehta, Inmaculada Martínez-Reyes, Peng Gao, Kathryn A. Helmin, Hiam Abdala-Valencia, Laura A. Sena, Paul T. Schumacker, Laurence A. Turka & Navdeep S. Chandel

• Regulatory T-cells (T-regs) are a sub-population of T cells (T cells being a kind of immune cell) which have immunosuppressive activities. They tend to down-regulate the induction and proliferation of effector T cells.
• In this study, the authors ablate complex III in T-regs of mice, and show that this induces fatal inflammatory disease early in life. 
• Mice lacking complex III in T-regs displayed a loss of ability to downregulate T-cell activity, without affecting T-reg proliferation and survival. 
• Loss of complex III in T-regs was associated with increased DNA methylation