#1
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#2

I was looking at the supplementaries and thought to upload this.

ijms-3252761-supplementary.pdf (211.6 KB)

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#3

Young are 20-40 and old are over 60.

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#4

I wonder if this might be the cause of death in mice even after repeated cellular reprogramming treatments in the Altos study.

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#5

My view is that “cellular reprogramming” as it is called is just a complicated way of trying to improve the mitochondria. It is the mitochondrial state that drives the genomic function (which proteins are produced) which creates the aging phenotype.

Cellular reprogramming adds the additional complications of dedifferentiation.

If it (reprogamming) does not increase the mitochondrial function sufficiently it will not actually fully rejuvenate the cells. SOX2, however, is quite powerful.

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#6

@John_Hemming @Paul_2.0

We know true, complete reprogramming that a mother does at the stage of when her egg has been fertilized is resetting the state of mitochondria to a young zero years old right?
(The baby does not start life with the state of mitochondria of his/her mother, but as a new born state right?)

So perhaps later improved generations of partial reprogramming can solve this?

And perhaps an earlier solve is mitochondrial transplants/transfusions?

Think @RapAdmin reported on that from the Buck Institute meeting he was at?

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#7

I would think that the mitochondrial age is something that iPSC researchers are taking a good look at. The science is young with a number of problems to solve.
Induced pluripotent stem cells are very close but not exactly the same as embryonic stem cells.

DNA methylation globally: Human iPS cells are highly similar to ES cells in their patterns of which cytosines are methylated, more than to any other cell type. However, on the order of a thousand sites show differences in several iPS cell lines. Half of these resemble the somatic cell line the iPS cells were derived from, the rest are iPSC-specific. Tens of regions which are megabases in size have also been found where iPS cells are not reprogrammed to the ES cell state.

https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell

From the paper John posted, new research shows the mitochondria aren’t the same either. I hadn’t seen that before.

Even that reprogramming isn’t complete to zero, some epigenetic marks get carried over or rewritten…and there’s imprinting to select either the father’s or mother’s DNA to be active.

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#8

Yes, but over the generations it’s getting reset on average back by the same amount that a generation aged after each new embryo/baby right?

I.e. it’s not like we have all the epigenetic aging back to Adam and Eve…. Or are you saying that each (mammalian) species is becoming less and less healthy for each generation that goes by?

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#9

The epigenetics get mostly reset right after the egg is fertilized but environmental conditions in the womb are constantly changing the epigenetic marks in the embryo.

“Reprogrammings that are both large scale (10% to 100% of epigenetic marks) and rapid (hours to a few days) occur at three life stages of mammals. Almost 100% of epigenetic marks are reprogrammed in two short periods early in development after fertilization of an ovum by a sperm. In addition, almost 10% of DNA methylations in neurons of the hippocampus can be rapidly altered during formation of a strong fear memory. After fertilization in mammals, DNA methylation patterns are largely erased and then re-established during early embryonic development. Almost all of the methylations from the parents are erased, first during early embryogenesis, and again in gametogenesis, with demethylation and remethylation occurring each time.”
“The establishment of most DNA methylation marks occurs in utero; however, a small percentage of epigenetic marks are dynamic and can change throughout a person’s lifetime and in relation to exposures. DNA methylation can be transmitted from parent to daughter cells, indicating that this form of epigenetic modification could represent a molecular mediator capable of propagating the memory of past cellular perturbations.”
“Methylation patterns of the germline and somatic cell lineages are established during early embryonic development. Methylation of CpG sites can also persist from the germline of one parent to the zygote, marking the region as being inherited from one parent or the other, known as genetic imprinting. Increasing evidence from animal models and human observational studies suggests that the ‘programming’ for various adverse health outcomes occurs during the in utero and early postnatal period, likely by disturbing DNA methylation marks.”
“A recent twin study indicated that among CpGs exhibiting variation, variation of 90% of the sites was explained solely by the individual’s unique environmental factors and only 10% of these sites were influenced by familial factors (genetic or shared environment) suggesting that some methylation marks change over time while others do not.”
“As a fertilized egg develops into a baby, dozens of signals received over days, weeks, and months cause incremental changes in gene expression patterns. Epigenetic tags record the cell’s experiences on the DNA, helping to stabilize gene expression. Each signal shuts down some genes and activates others as it nudges a cell toward its final fate. Different experiences cause the epigenetic profiles of each cell type to grow increasingly different over time. In the end, hundreds of cell types form, each with a distinct identity and a specialized function. Epigenetic tags give the cell a way to “remember” long-term what its genes should be doing.”

"We used to think that a new embryo’s epigenome was completely erased and rebuilt from scratch. But this isn’t completely true. Some epigenetic tags remain in place as genetic information passes from generation to generation, a process called epigenetic inheritance.

Epigenetic inheritance is an unconventional finding. It goes against the idea that inheritance happens only through the DNA code that passes from parent to offspring. It means that a parent’s experiences, in the form of epigenetic tags, can be passed down to future generations.

As unconventional as it may be, there is little doubt that epigenetic inheritance is real. In fact, it explains some strange patterns of inheritance geneticists have been puzzling over for decades."

“At certain times during development (the timing varies among species), specialized cellular machinery scours the genome and erases its epigenetic tags in order to return the cells to a genetic “blank slate.” Yet, for a small minority of genes, epigenetic tags make it through this process and pass unchanged from parent to offspring. In mammals, about 1% of genes escape epigenetic reprogramming through a process called Imprinting.
Epigenetic marks can pass from parent to offspring in a way that completely bypasses egg or sperm, thus avoiding the epigenetic purging that happens during early development.”

“Most of us were taught that our traits are hard-coded in the DNA that passes from parent to offspring. Emerging information about epigenetics may lead us to a new understanding of just what inheritance is.
Epigenetic inheritance adds another dimension to the modern picture of evolution. The genome changes slowly, through the processes of random mutation and natural selection. It takes many generations for a genetic trait to become common in a population. The epigenome, on the other hand, can change rapidly in response to signals from the environment. And epigenetic changes can happen in many individuals at once. Through epigenetic inheritance, some of the experiences of the parents may pass to future generations. At the same time, the epigenome remains flexible as environmental conditions continue to change. Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment - without changing its DNA code.”

Collected from around the web in snippets.

#10

The oocytes mitochondria go through a bottleneck that reduces heteroplasmy and the weaker zygotes simply fail. To protect the eggs from metabolism they are created in an embryo.

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#11

Interesting tidbit for trivial pursuit.

" In addition, mtDNA is mainly maternally inherited: it passes down the female line. This is because the sperm provides almost no cytoplasm (and hence no mitochondria) to the fertilized egg. The egg has thousands of mitochondria and it is these that are passed to the developing embryo.”

#12

Is they = mitochondria in here?

#13

Yes, and what’s less known is in rare cases one can get mitochondria from biological father (but almost always from mother).

So your mitochondria are from “Eve”…

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#14

How mitochondria age - from the paper in the 1st post.

The free radicals theory of aging posits that mitochondria are central to the process, serving as both a source and target of reactive oxygen species (ROS) [4]. As we age, oxidative stress increases, potentially damaging proteins, lipids, and DNA, which in turn impacts mitochondrial function. Post-mitotic cells, such as neurons, are highly susceptible to oxidative damage and mitochondrial dysfunction because they primarily rely on the OxPhos system to meet their substantial energy demands. At the cellular level, the activity of the respiratory chain seems to reduce with increasing age, thus increasing electron leakage and decreasing ATP production [21]. The cell produces less energy, and at the same time levels of oxidative stress rise, causing damage to other cellular metabolites [4,22]. Of note, ROS have also been shown to extend longevity by acting as a signalling molecule, according to the concept of “mitohormesis” or “oxidative eustress” [23]. This theory suggests that mild mitochondrial stress could protect the cells against subsequent perturbations. When reactive oxygen species (ROS) are produced in excess and overpower the cell’s antioxidant defenses, a condition known as oxidative distress occurs [24]. This can result in the damage of proteins, lipids, and DNA, leading to impaired cellular functions, accelerated aging, and an increased risk of diseases such as cancer, neurodegenerative disorders, and cardiovascular diseases. Interestingly, low levels of ROS were implicated in maintaining the quiescent state of hematopoietic stem cells (HSCs), while increases in ROS serve as signalling molecules to support stem cell differentiation [25]. Excessive levels of ROS were shown to create an oxidative microenvironment in pathophysiological states, such as aging leading to cellular damage

#15

It is the eggs, but also the mitochondria in those eggs. The thing to remember about mitochondria is that they have a lifecycle of their own.

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#16

What they miss in this is that as ATP/O efficiency goes down, the mitochondrial membrane potential godes down and also citrate efflux goes down. That affects how the nucleus produces proteins in that it produces less proteins and different splices.

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#17

Had to do a deep dive into mitochondria. I had thought that the key to mitochondrial health and producing more ATP was in making more mitochondria, and certainly this is necessary for cell division, however, mitochondria cannot be created de novo but only by splitting in two (fission). And fusing 2 mitochondria together looks even more beneficial for ATP productivity.

Fusion occurs when two adjacent mitochondria join, while fission separates one mitochondria into two (SebastiĂĄn and Zorzano, 2018) (Fig. 1). These two events permanently counterbalance each other; the inactivation of one leads to unopposed action by the other and the subsequent imbalance controls mitochondrial structure.

Mitochondrial fusion tends to lead to an increase in bioenergetics efficiency, maintaining ATP production even upon limited nutrients and therefore allowing the cell to maintain viability (Gomes et al., 2011; Rambold et al., 2011). Meanwhile, mitochondrial fragmentation (fission) is associated with increased oxidative stress, mitochondrial depolarization, and reduced ATP production (Jheng et al., 2012). The decreased bioenergetics efficiency may serve as a protective mechanism from the detrimental effects associated with nutrient overload.

Fusion allows the exchange of mitochondrial contents between adjacent mitochondria which facilitates functional complementation in the face of mitochondrial deficits (Liu et al., 2009). In contrast, fission allows an equal distribution of the mitochondrial proteome and mtDNA in two daughter mitochondria during mitochondrial biogenesis (Mishra and Chan, 2014). Fission also functions by segregating dysfunctional and superfluous mitochondria for degradation through mitochondrial autophagy

Mitochondrial fusion is important for maintaining mtDNA levels and mtDNA fidelity.
In addition, reducing mitochondrial fusion by conditionally ablating mitofusins in mouse skeletal muscle or heart results in profound reductions in mtDNA content, great accumulations of mtDNA mutations, and development of mitochondrial myopathy in both muscle and heart. Overall, these results demonstrate the beneficial effects of fusion in safeguarding mtDNA integrity, thereby highlighting fusion as a potential therapeutic target for aging and mtDNA-related diseases.

Urolithin A treatment in C. elegans induces mitochondrial fragmentation (fission) and autophagy-dependent mitochondrial removal (Ryu et al., 2016). In aged mice, urolithin A stimulates autophagy in gastrocnemius muscle and prevents age-related decline of muscle function (Ryu et al., 2016). In summary, these findings suggest that targeting mitochondrial fission-mitophagy axis provides promising therapeutic choices to benefit organismal health and lifespan.

1-s2.0-S0047637420300063-gr3

Fig. 3. The role of mitochondrial fission and fusion in metabolic signaling pathways. Generalized and simplified summary of the main pathways linking nutritional state with mitochondrial dynamics and their ultimate phenotypic outcome. AMPK, insulin/IGF, and mTOR nutrient signaling pathways constitute a core network in mammalian cells to coordinate metabolism and regulate lifespan. Depending on the availability of nutrients, these signaling pathways are differentially switched on or off, corresponding to specific mitochondrial morphologies. For example, under the condition of starvation, AMPK is activated, while insulin/IGF and mTOR signaling are suppressed. This change typically favors mitochondrial fusion, which is associated with major beneficial effects such as prolonged lifespan, improved insulin sensitivity, and enhanced glucose tolerance. In contrast, nutrient excess activates insulin/IGF and mTOR signaling but represses AMPK. This leads to an activation of mitochondrial fission, which is associated with a number of human pathologies such as aging, cardiomyopathy, obesity, and diabetes. It should be noted that these responses are not uniform and are highly context-dependent.

Concluding remarks

Mitochondria are major crossroads of catabolic and anabolic metabolism and signaling hubs that integrate diverse cellular signals to regulate cell growth, differentiation, vitality, and death. As such, mitochondrial dysfunction is one of the classical hallmarks of aging (Lopez-Otin et al., 2013). Although knowledge of how mitochondria affect and are affected by aging has grown considerably in recent decades, there is still much to untangle with regards to how the mitochondria influences health and aging in complex organisms. Considering this question from the perspective of mitochondria network dynamics, the following conclusions emerge: (1) mitochondrial form and function are closely interlinked, and the dynamic nature of mitochondrial morphology permits mitochondria to adjust their functions in response to intrinsic and extrinsic signals through a prompt morphological rearrangement; (2) divergent cellular signaling pathways that control the rate of aging such as insulin/IIS, LET-363/TOR, AMPK, and mitochondrial dysfunction-mediated longevity pathways correspond to specific mitochondrial forms. (3) mitochondrial fission and fusion are integral to mitochondrial behavior, but the significance of each process to mitochondrial and cellular functions is highly context-dependent. We propose that remodeling mitochondrial morphology is likely the common strategy adopted by various signaling pathways to impinge on mitochondrial activities and therefore exert their influences on cellular bioenergetic homeostasis. In this regard, future investigations should focus on revealing regulatory mechanisms underpinning mitochondrial morphological changes in aging and aging-related pathologies as well as the downstream implications of the mitochondrial network in aging contexts. A better understanding of these principles will provide a promising opportunity to slow the progress of age-related diseases by targeting the mitochondrial network.

https://www.sciencedirect.com/science/article/pii/S0047637420300063

#18

The pathways of mitophagy for quality control and clearance of mitochondria | Cell Death & Differentiation.

Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration.

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#19

Good article. It also has a section on mitochondrial fission/fusion as well as maternal/paternal inheritance of mitochondria.

Fission and fusion, as well as mitochondrial trafficking on actin (in yeast) or the microtubule cytoskeleton (in higher organisms) enable the cell to adjust mitochondrial distribution to changing local needs. Mitochondrial fission and fusion are regulated by members of a family of conserved large GTPases, initially identified in yeast.50, 51 The dynamin-like GTPase, dynain-related protein 1 (Drp1) (Dnm1 in yeast), mediates fission by forming a multimeric complex that wraps around the outer membrane of mitochondrial tubules and exerts mechanical force to produce membrane scission. In contrast to fission where mitochondria are divided using only an outer membrane apparatus, two distinct machineries, Mitofusin 1 and 2 (Fzo in yeast) and optic atrophy 1 (Opa1) (Mgm1 in yeast), are required for fusion of the outer and inner membranes, respectively. Mitochondrial fusion is also regulated by mitochondrial motility, although less directly; stationary mitochondria are less likely to encounter another mitochondrion with which to fuse.52 A critical function of fusion and fission is to allow for efficient distribution of mtDNA and proteins throughout the mitochondrial network.51 Even brief fusion events can allow extensive exchanges of mitochondrial content. By following the fate of individual photo-labeled mitochondria, Twig and co-workers53 have shown that a fusion event is often followed by fission, creating daughter mitochondria with uneven mitochondrial potentials. Whereas the daughter mitochondrion with the healthier membrane potential will continue to participate in fusion and fission cycles with the mitochondrial reticulum, the depolarized daughter mitochondrion is unlikely to undergo fusion and is often degraded through mitophagy.

Depolarization causes the loss of Opa154 and Mitofusins (Mfn1 and 2),55, 56, 57 proteins necessary for the fusion of the inner and outer membranes of mitochondria, and thereby promotes mitochondrial fragmentation. In agreement with the essential role of fission in mitophagy, a yeast genetic screen revealed that Dnm1, the yeast homolog of Drp1, is essential for mitophagy.20 Similarly in mammals, genetic manipulations that cause excessive fusion, such as overexpression of Opa1 or dominant-negative Drp1, preclude autophagic degradation of mitochondria.58 This protection from autophagy by hyperfusion occurs physiologically during certain types of starvation-induced autophagy, in which a fused mitochondrial network protects mitochondria from degradation.59 In summary, a shift in the balance of mitochondrial dynamics towards increased fission and decreased fusion promotes segregation of damaged mitochondria and facilitates their clearance by mitophagy.

Two groups have recently described a novel developmental role for mitophagy in the elimination of paternal mitochondria from fertilized oocytes (Figure 3c).13, 14 In most eukaryotes, only maternal mitochondrial DNA is inherited, although sperms do contain mitochondria that are present in the oocyte immediately after fertilization. These paternal mitochondria are rapidly destroyed, although the evolutionary advantage this confers is unclear.

What’s wrong with the father’s mitochondria? That seems unfair.

#20

I think there is something from the father that is needed for the placenta

Where if that is lacking the placenta does not support a healthy fetal development

(And that the idea is that evolution hence ensured that fathers are needed in mammals (and many other species) and our females cannot produce offspring by only tapping into the DNA they have themselves - as some other species, think some reptiles, can do if males are lacking).

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