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Mitochondrial peptides - drivers of longevity?

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Luis Almeida Nov 27, 2020
Mitochondria have their own genome and ribosomes. This means that they can make certain proteins independently of the rest of the cell. While most of these proteins are part of the electron transport chain – what enables mitochondria to do respiration – some other parts of the mitochondrial genome encode what are known as mitochondrial-derived peptides. As a concept, these mitochondrial peptides are quite cool: they are produced inside the mitochondria of cells, and can then exit those cells and be sensed by other neighboring or distant cells. In other words, they can act as messengers from the mitochondria of certain cells to other distant cells. The most widely studied mitochondrial-derived peptide is Humanin, which has been reported as having a wide range of cellular and organismal metabolic effects. For instance, it has several metabolic effects such as reducing weight and visceral fat, while promoting insulin release. Further, humanin has been implicated in diseases such as type 2 diabetes, cardiovascular disease, memory loss, amyotrophic lateral sclerosis, stroke, and inflammation. In most species (including humans), humanin levels in circulation decrease with age. Furthermore, a humanin analogue has displayed neuroprotective effects in vitro and in mice. Particularly, mice treated with this humanin analogue displayed improved cognitive function. These pilot results have prompted researchers to test if humanin could delay aging. Unfortunately, their results have only been reported in worms and were not replicated in mice, and for that reason should be taken with a grain of salt. Still, worms overexpressing humanin lived slightly longer, but were shorter, laid fewer eggs, and had lower levels of fat. When trying to determine if humanin treatment improved lifespan in mice, the authors observed no advantage compared to untreated mice. However, they postulate that this may be due to the short half-life of humanin (30 minutes), which may have contributed to insufficient physiological concentrations to achieve the desired effect. In the future, they are planning to determine if a mouse strain, genetically-modified to overexpress humanin, can survive longer. With that said, it would be interesting to also think of the following:
1 - Do mitochondrial-derived peptides play a role in aging in mammals, particularly in adults?
2 - Can these mitochondrial-derived peptides be decreased by mitochondrial oxidative stress, which may help explain the link between oxidative stress and aging?
3 - How does one explain that reduction of mitochondrial protein synthesis (which should encompass mitochondrial-derived peptides) also leads to an increased lifespan in worms?
4 - If these peptides are indeed able to delay aging, how do we get around the issue of short half-life?
Would be interested in reading your thoughts!

[1]D'Souza, A.R. and M. Minczuk, Mitochondrial transcription and translation: overview. Essays Biochem, 2018. 62(3): p. 309-320.

[2]Merry, T.L., et al., Mitochondrial-derived peptides in energy metabolism. American Journal of Physiology-Endocrinology and Metabolism, 2020. 319(4): p. E659-E666.

[3]Lee, C., K. Yen, and P. Cohen, Humanin: a harbinger of mitochondrial-derived peptides? Trends in Endocrinology & Metabolism, 2013. 24(5): p. 222-228.

[4]Kim, S.J., et al., Mitochondrially derived peptides as novel regulators of metabolism. J Physiol, 2017. 595(21): p. 6613-6621.

[5]Gong, Z., E. Tas, and R. Muzumdar, Humanin and age-related diseases: a new link? Front Endocrinol (Lausanne), 2014. 5: p. 210.

[6]Muzumdar, R.H., et al., Humanin: a novel central regulator of peripheral insulin action. PLoS One, 2009. 4(7): p. e6334.

[7]Yen, K., et al., Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans. Sci Rep, 2018. 8(1): p. 14212.

[8]Yen, K., et al., The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging (Albany NY), 2020. 12(12): p. 11185-11199.

[9]Houtkooper, R.H., et al., Mitonuclear protein imbalance as a conserved longevity mechanism. Nature, 2013. 497(7450): p. 451-7.

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Subash Chapagain
Subash Chapagaina year ago
In regard to whether the MT peptides (especially Humanin) can play a crucial role in ageing in humans, the question definitely needs some rigorous experimental investigation. If they do (which is very much likely- collaboratively, if not independently, with other nuclear derived proteins), then there is a high chance that the answer to your second question is a big yes. Owing to the eternal fate of mitochondria to be involved in energy production, the production of ROS and hence the amassing oxidative stress is obvious. This oxidative stress can be expected to affect the functioning of these peptides.

In case,in the future, a solid evidence for Mt-peptides to be involved in (anti)ageing mechanisms in humans is established and that the problem of their depletion due to oxidative stress (which theoretically and logically is likely to be the case) identified, then there might be a possible approach of addressing this problem by using the natural cellular mechanism of autophagy. Autophagy, the cohort of cellular processes dedicated for breaking down and recycling damaged structures and unwanted proteins in cells can slow aging and allow individuals to live longer. Autophagy aggressively removes harmful (or malfunctioning) cellular components, and reduces the time period they exist in the cells, thereby helping cells and tissues function better.

What is even more exciting in regard to Mt-peptides is that the peptide Humanin (HN) could act as an endogenous Chaperone Mediated Autophagy (CMA), activator, a study from 2018 had shown. [1] The group showed that (cultured) cell types including cardiomyoblasts, primary cardiomyocytes and dopaminergic neuronal cells are protected by Humanin from oxidative stress-induced cell death in a CMA dependent manner. This was evident from the fact that CMA-incompetent (LAMP-2A knockdown) cells did not show protective effects. Both endogenous and exogenous Humanin localize at the lysosomal membrane where they co-operate to enhance CMA efficiency where it acts by stabilizing binding of the HSP90 chaperone to the upcoming substrates at the cytosolic end of lysosomal membrane. This was the first reporting of mitochondrial signals controlling CMA. It is proposed by the researchers that meanwhile mitochondria generates ROS from metabolis, it simultaneously generates signals like Humanin peptide in order to counteract the oxidative insults by activating CMA. An ageing related link can be drawn from the observation that both Humanin and CMA decline with age. [2]

Also, it is interesting that the genetic correction of the CMA defect in livers from old mice can effectively improve hepatic homeostasis, rendering higher resistance to stress and improved overall organ function. [3] With these findings reported, now the next question would be if the interventions aimed to enhance Humanin peptide levels could have a similar effect and protect against oxidative stress. Also, whether this function is unique to Humanin or other mitochondrial encoded proteins also share the feature of protective role needs to be investigated in detail. May be one starting point to dig more into the implications would be to consider diseases like Parkinson’s disease which are age-related.

Moving on to your third question as to the anomalous observation where it is seen that the inhibition of mitochondrial translation (which means the Humanin is also eventually inhibited) leads to extended lifespan, it indeed is hard to pin-point the exact causal connections. The paper you have cited has detailed extensively that the mitochondrial ribosomal proteins (Mrps5 and Mrp protein family) are the main actors in the metabolic lifespan regulation. [4] The paper has conclusively proposed that the Mrp-lifespan connection is not organism-specific, rather an evolutionarily phenomenon, which of course demands further scrutiny. What about non ribosomal proteins of mitochondrial origin? Are they too a part of an evolutionarily conserved way of cellular homeostasis maintenance?

Finally, to address your final query on how we could attain more stable peptides with longer half lives, there are a number of ways to achieve that, it seems. The most commonly practiced approach to half-life enhancement is PEGylation where polyethylene glycol (PEG) chains are attached to the peptides covalently. However this approach might lead to hypersensitivity, antibody formation and bioaccumulation. [5] Another possible way of increasing half-life of proteins and peptides in vivo is to design chemical moieties into the peptides such that it conveys protraction by binding to albumin. SInce human serum albumin (HSA) is a very stable molecule in plasma that is sterically from proteolytic degradation as well as protected from renal filtration (due to its large 66kDa size), albumin binding of these peptides/proteins can have extended lifespan, in principle of up to 19 days half-life of albumin. [6] Apart from these wet-lab techniques, in-silico approaches can be applied to design the peptide alterations that can significantly increase half-life of the synthetic peptides. [7]

References:
1. Zhenwei Gong, Inmaculada Tasset, Antonio Diaz, Jaime Anguiano, Emir Tas, Lingguang Cui, Regina Kuliawat, Honghai Liu, Bernhard Kühn, Ana Maria Cuervo, Radhika Muzumdar; Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol 5 February 2018; 217 (2): 635–647. doi: https://doi.org/10.1083/jcb.201606095

Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, et al. (2009) Humanin: A Novel Central Regulator of Peripheral Insulin Action. PLOS ONE 4(7): e6334. https://doi.org/10.1371/journal.pone.0006334

3 Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 2008;14:959-965.

4.Houtkooper, R.H., et al., Mitonuclear protein imbalance as a conserved longevity mechanism. Nature, 2013. 497(7450): p. 451-7.


5.van Witteloostuijn, S. B.; Pedersen, S. L.; Jensen, K. J. Half-Life Extension of Biopharmaceuticals Using Chemical Methods: Alternatives to PEGylation. ChemMedChem 2016, 11, 1– 23, DOI: 10.1002/cmdc.201600374

6.Sleep, D.; Cameron, J.; Evans, L. R. Albumin as a Versatile Platform for Drug Half-Life Extension. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 5526– 5534, DOI: 10.1016/j.bbagen.2013.04.023

7.Sharma, A., Singla, D., Rashid, M. et al. Designing of peptides with desired half-life in intestine-like environment. BMC Bioinformatics 15, 282 (2014). https://doi.org/10.1186/1471-2105-15-282