Mitochondria and aging: A role for the mitochondrial transition pore?

Mathieu Panel, Bijan Ghaleh, Didier Morin

https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12793

The mitochondrial permeability transition pore (mPTP) is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stroke. Induction of the permeability transition pore, referred to as the mitochondrial membrane permeability transition (mPT), can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting.

Recently, the mPTP has been implicated in the development of the ageing process.

In this paper, the authors review the potential role of mPTP in normal aging and in age-associated diseases.

CALCIUM HOMEOSTASIS, mPTP AND AGEING                                                                    Elevated matrix calcium was the first factor described to activate mPTP opening, and aging alters cytosolic calcium handling. This has been sown in the heart, where aging impairs the myocardial calcium transport system and calcium storage capacities. This was also confirmed in myocytes isolated from human right atria.   

ROS GENERATION, mPTP AND AGEING                                                                              

It is well known that mitochondria are producers of reactive oxygen species (ROS). Evidence suggests that aging involves a change in ROS regulatory processes encompassing a decline in mitochondrial function and an increase in ROS generation. The possible link between ROS production and mPT during ageing is that ROS decrease the calcium concentration needed for mPTP opening and thus sensitize it. This was observed with cardiolipin, a phospholipid that is specific of mitochondria and is susceptible to lipid peroxidaztion by ROS. Oxidized cardiolipin was shown to sensitize heart mitochondria to mPTP opening, and the level of oxidised cardiolipin increases with aging.

MEMBRANE POTENTIAL, mPTP AND AGEING

Several studies have shown that the mitochondrial membrane potential is lower in aged cells. This may have consequences on mPTP opening, as mPTP is a voltage-dependent channel which tends to open upon depolarization. It has been shown in vitro that depolarization induces mPTP opening when mitochondria have been suitably loaded with calcium.

NAD+, mPTP AND AGEING

Several data suggest that aging reduces cellular nicotinamide adenine dinucleotide (NAD+). This was observed in mice, C. elegans and human tissues. Conversion of NAD+ to NADH plays a key role in mitochondrial metabolism. A drop in NAD+ cellular levels can therefore limit NADH generation.  This decreases mitochondrial membrane potential, which increases the frequency and duration of mPTP opening. In turn, mPTP opening causes the release of NAD+ from mitochondria and its depleiton, therefore inducing a vicious circle.
Another important consequence of mitochondrial NAD+ depletion is the inhibition of mitochondrial sirtuin (SIRT, a class of deacetylases) activity, especially SIRT3. This enzyme plays a critical role in the protection of mitochondria and, more particularly, it was shown to inhibit mPTP opening.

In conclusion, a large number of studies demonstrated that the mPTP is more sensitive to opening in aged animals and in aging-associated diseases. However, doubts persist  and definitive experimental proofs of mPTP involvement have to be provided to demonstrate whether it is a cause or a consequence of aging.

Quantification of subclonal selection in cancer from bulk sequencing data

Williams MJ, Werner B, Heide T, Curtis C, Barnes CP, Sottoriva A, Graham TA

https://www.nature.com/articles/s41588-018-0128-6

• The authors investigate intratumoral genetic heterogeneity by performing Bayesian inference on a population-genetics model of asexual evolution, using data from high-coverage bulk sequencing data. The model combines a generative model for tumour development with an error model for sequencing.
• Previous work by the authors showed that, under a neutral evolutionary model, the variant-allele fractions (VAFs) (i.e. the percentage of genomes which are mutated in a particular allele) follow a power-law distribution. Subsequent work by the authors showed that by modelling spatial effects and selection, the authors could infer whether a particular variant was neutral or non-neutral
• In this work, the authors use a stochastic branching process model, whereby cells divide and die with particular rates, and acquire de novo mutations upon division. Mutant subclones are assigned a fitness advantage, which is related to the ratio of replication rate of the mutant to the background host population. Clones which have a selective advantage induce an additional peak in the distribution of VAFs.
• The mean VAF of a particular cluster is a measure of its relative size within the tumour; the total number of distinct mutations in the cluster is a measure of its age, since older subclones have had more time to accrue mutations. These two pieces of information allow the replication rate of the particular subclone to be constrained, and its selective advantage to be inferred. 
• Note that mutations can hitchhike with the actual driver event, so it is not necessarily the case that all mutations with a surprisingly high VAF cause a selective advantage. The driver event may not necessarily even be genetic in origin.
• Using this framework, the authors discover detectable subclones which were consistently present, with a fitness advantage >20%.

Hematopoietic stem cell fate through metabolic control

https://www.sciencedirect.com/science/article/pii/S0301472X18302650

Kyoko Ito and Keisuke Ito

•  Hematopoitic stem cells (HSCs) exist in bone marrow and give rise to a number of different cell types, see here. These stem cells are usually non-dividing (quiescent) until there is a need to i) renew the pool of HSCs or ii) generate new differentiated cells. HSCs can divide symetrically (giving rise to two new HSCs), divide asymmetrically (creating 1 differentiated cell and 1 HSC) and divide to generate 2 differentiated cells (symmetric commitment).
• The authors discuss a study where single HSCs were purified. They found that activation of the PPAR (peroxisome proliferator-activated receptor)- fatty acid oxidation pathway promotes HSC symmetric division through enhanced Parkin recruitment in mitochondria. This pathway activates enhanced mitophagy in HSCs. The authors suggest that enhanced mitophagic clearance of damaged mitochondria is necessary for self-renewing expansion of HSCs.
• Impaired autophagy has been shown to result in HSC exhaustion, and conditional depletion of Atg7 can lead to lethal anemia
• Defective autophagy by the ablation of Atg12 accelerates blood aging phenotypes
• The authors discuss another study which found that loss of authophagy in HSCs causes accumulation of mitochondria and an activated metabolic state, which drives differentiation. These features are shown in HSCs from aged mice. They suggest that autophagy actively suppresses HSC metabolism by clearing active, healthy mitochondria, to maintain quiescence and stemness. [Thought. The idea of actively degrading healthy mitochondria for the purpose of slowing metabolism seems drastic/wasteful?]
• Excessive mitophagy is associated with enlarged HSC pools and blocked lineage commitment. The authors argue that mitophagy levels must be controlled to ensure maintenance of HSCs and appropriate differentiation.

Power grid protection of the muscle mitochondrial reticulum.

https://www.ncbi.nlm.nih.gov/pubmed/28423313

Brian Glancy, Lisa M. Hartnell, Christian A. Combs, Armel Femnou, Junhui Sun, Elizabeth Murphy,

Sriram Subramaniam and Robert S. Balaban.

THE DRAWBACK OF THE MITOCHONDRIAL NETWORK

Cellular mitochondrial networks allow for sharing of metabolites and proteins as well as mitochondrial DNA, and also provide a rapid conductive path for the distribution of potential energy.

However, this extensive coupling presents a major risk as local failures can also spread quickly over the entire network and compromise cellular energy conversion.

Like many power networks that physically segment elements with circuit breakers, similar strategies may be in place to protect cells with coupled mitochondrial networks from propagating local failures.

EXISTENCE OF SUBNETWORKS

Using 2-to-4 month old mice, the authors demonstrate the existence a physically and electrically connected mitochondrial reticulum arranged into longitudinal subnetworks within the cardiac cell.

Each subnetworks comprises many mitochondria and subnetworks are linked through abundant contact sites at highly specific intermitochondrial junctions, IMJs.

(A junction is defined by the close apposition of both the inner and outer membranes of two adjacent mitochondria with high electron density).

PROTECTIVE FUNCTION OF THE SUBNETWORKS

This arrangement of mitochondria into several regional subnetworks as opposed to a single, cell-wide network limits the spread of localized mitochondrial dysfunction to within defined volumes.

In both cardiac and Skeletal muscle subnetworks, a rapid electrical and physical separation of malfunctioning (depolarised) mitochondria occurs, consistent with detachment of IMJs, allowing the remaining mitochondria to resume normal function within seconds. This limits the impact of mitochondrial dysfunction.

These rapid alterations in mitochondrial connectivity allow muscle cells to respond to local dysfunction and restore the energy distribution systems to the remainder of the cell.