Diet impact on mitochondrial bioenergetics and dynamics

http://journal.frontiersin.org/article/10.3389/fphys.2015.00109/full

Rosalba Putti, Raffaella Sica, Vincenzo Migliaccio and Lillà Lionetti

 

In this study they investigate the effect of two different fat dietary sources (saturated (HL diet) vs polyunsaturated (HFO diet) omega 3 ) on mitochondrial dynamics and function in rat liver and skeletal muscle. The consequences of starvation and caloric restriction (CR) are also discussed.

The high fat diet rich in saturated fatty acid (HL diet) decreases mitochondrial function and increases ROS production. Mitochondria became more fragmented. Mitochondria do become more efficient due to a decrease in proton leak. An increase in energy efficiency reduces energy expenditure and can contribute to obesity development. In several studies it has been suggested that decreases in Mfn2 lead to decreases in proton leak. Mfn2 has also been linked to regulation of in vivo insulin resistance. Increased mitochondrial fragmentation induced by HL diet may be an adaptive cellular response to increase oxidation of surplus dietary fatty acids, which results in higher ROS production.

In contrast to the HL diet, the HFO diet rich in polyunsaturated fatty acids seems to improve mitochondrial function. ROS production is reduced, and increased mitochondrial fusion is seen. HFO diet also leads to a mild mitochondrial uncoupling due to enhanced expression of uncoupling protein 2. Mitochondrial efficiency is thus decreased, which may explain the decrease in ROS and observed increase in fatty acid utilization. There was less weight gain in rats with HFO diet compared to rats with HL diet.

Opposite effects on mitochondrial dynamics are seen for two types of nutrient deficiency, starvation and caloric restriction (CR):

Upon starvation, mitochondria fuse, has been associated with increases in ATP production. The fusion of mitochondria during starvation has been suggested to maximize energy production to sustain the cell during nutrient deprivation.

On the other hand, CR (e.g. mice submitted to 40% CR for 6 months) leads to mitochondrial fission. Mitochondrial biogenesis also increases. The larger number of mitochondria seen was linked to a reduction in oxygen consumption, membrane potential and ROS. Levels of ATP production were no different in CR conditions vs. control. It is like the cell increases the number of mitochondria so that each mitochondrion works less hard, which then decreases ROS. Having mitochondria fragmented also means that dysfunctional mitochondria can be more easily degraded.

What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research

 http://onlinelibrary.wiley.com/doi/10.1002/bies.201400188/full

 Hanne Hoitzing, Iain G. Johnston and Nick S. Jones

Mitochondria are dynamic organelles: sometimes they are fragmented, sometimes they form giant fused networks across the cell, and sometimes they take on intermediate shapes. What is the reason for having these different possible morphologies?

In this paper we discuss the function of large fused mitochondrial networks. Some hypotheses existing in the literature are being discussed, and some new ones are proposed. A mathematical perspective is taken. Coarse-grained models, simulations and estimations are used to try to gain insights. To enable a mathematical description of mitochondrial fusion, the terms microfusion, mesofusion, static hyperfusion and dynamic hyperfusion are introduced. Improvements for models are suggested, and future experiments are proposed.

Among the insights found are the possibilities that selective fusion alone leads to an increase in mitochondrial quality control; that increased fusion may have non-linear effects on the diffusion rate of proteins; that the effect on membrane potential of fusion may be more complicated than a simple averaging; and that fusion can act to dampen biochemical fluctuations.

Cardiolipin is a key determinant for mtDNA stability and segregation during mitochondrial stress

http://www.sciencedirect.com/science/article/pii/S0005272815000572#bb0060

Luis Alberto Luévano-Martínez,Maria Fernanda Forni,Valquiria Tiago dos Santos,Nadja C. Souza-Pinto and Alicia J. Kowaltowski

Cardiolipin makes up about 15% of the phospholipid content of the mitochondrial inner membrane. Cardiolipin is known to stabilize ATP synthase dimers and respiratory chain super complexes, and is able to promote cristae-like structures by responding to pH gradients.

In this paper, they investigate the role of cardiolipin in the cellular response to mitochondrial stress in yeast. A genetic model which lacks the cardiolipin synthase gene is used.

Results show that cells lacking cardiolipin have increased levels of PG, the precursor of cardiolipin. In optimal growth conditions, cells without cardiolipin show no defects in respiration, whereas under thermal stress these cells show decreases in both basal and maximal respiratory rates. Thermal stress reduces the amount of respiratory chain complexes, including subunits encoded by mtDNA, this suggests that lack of cardiolipin may lead to mtDNA instability. Further results suggest that mtDNA indeed becomes more prone to stress-induced damage when no cardiolipin is present.

Cardiolipin may be involved in mtDNA segregation during budding.

MtDNA is normally anchored to the inner membrane, and perhaps cardiolipin plays a role in this anchoring. The inner membrane of mitochondria in yeast in composed of phosphatidylcholine (PC, about 38%), phosphatidylethanolamine (PE, 24 %), phosphatidylinositol (16%), cardiolipin (16%), phosphatidylserine (PS, 4%) and phosphoatidic acid (1.5%). In the paper they show that isolated nucleoids bind more to cardiolipin than to its precursor PG. No significant binding is observed to PC. Also when nucleoids isolated from mammalian cell lines were used, affinity for binding to cardiolipin was higher than binding to any of the other phospholipids. Further results suggest that mtDNA can anchor to the inner membrane in the absence of cardiolipin under control conditions, but not under thermal stress.

Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness

http://www.sciencemag.org/content/early/2015/04/01/science.1260384.long

Pekka Katajisto, Julia Döhla, Christine Chaffer, Nalle Pentinmikko, Nemanja Marjanovic, Sharif Iqbal, Roberto Zoncu, Walter Chen, Robert A. Weinberg, David M. Sabatini

The amount of mitochondrial content in a stem cell is thought to influence its tendency to differentiate. In this study, the authors use stemlike cells (SLCs), expressing photoactivatable green fluorescent protein (paGFP), to investigate the effect of protein aging. PaGFP only fluoresces after exposure to UV light. After UV exposure, and allowing the cells to age, old proteins fluoresce whereas new proteins do not. The authors tag a particular mitochondrial protein (Omp25) with paGFP and find that stem cells apportion the >10 hour old proteins asymmetrically between daughters, by a factor of ~5.6. This effect was not found for membrane proteins of other organelles, and not found at all in non-stem cells.

The authors probe this further, by using mitochondrial proteins fused to a Snap-tag. This method allows precise temporal labelling: young proteins appear green and proteins which are 10h old appear red. Interestingly, they find that young proteins are mainly found in the periphery of the cell. Whilst old mitochondria were asymetrically partitioned, young mitochondria were more uniformly distributed between daughters. They found that this asymmetry indicated the formation of two lineages amongst the daughters: daughters with mainly young mitochondria were more stem-like whereas those with old mitochondria tended to differentiate.

Finally, the authors sought to determine the cause of this asymmetry. Membrane potential was investigated, as this is known to correlate with stemness properties. Although they did indeed find that more stem-like cells tended to have higher ΔΨm, alterations of ΔΨm with an uncoupler had no effect on age-selective segregation, so this appears to be an effect rather than a cause of the age asymmetry. However, upon inhibition of Parkin (a pro-mitophagy protein) or Drp1 (pro-fission), daughter cells tended to inherit old and young mitochondria more symmetrically. Thus the authors suggest that perturbations which challenge mitochondrial quality control tend to remove this age-asymmetric partitioning, which maintains stemness properties.