Mitochondrial Deletions Matter in the Heart: another mosaic piece gets us closer to a solution

Here, I will discuss a recent paper by Baris, ..., Wiesner et al. (1). This work is from a Cologne group and the renowned “Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)”.

In the discussion the authors describe their hypothesis thusly:
Tissues of aged mammals display respiratory mosaicism, i.e., few cells with severe mitochondrial dysfunction embedded into normal tissue. This was shown for heart, skeletal muscle of the limbs and extraocular muscle, substantia nigra, and liver (reviewed in Larsson, 2010). However, it was unclear whether this mosaic phenotype is responsible for causing any of the typical aging-related symptoms of organ dysfunction.

Of course, the interested reader will note that it was not at all "unclear". The evidence is certainly controversial, particularly in humans/Rhesus monkeys, but by no means non-existent. I am not a fan of overselling and plenty of data by Aiken-McKenzie and others supports the idea (c.f. ref. 3 and start from there). One should give credit when it’s due, which is what the editorial by Khrapko et al. does (2). The paper by Baris et al. while interesting is certainly not any more definitive than the data we already have. However, it does clarify some controversy surrounding the TWINKLE KO model of accelerated deletion accumulation.
Baris et al. looked at a heart- and muscle-specific, dominant-negative K320E-TWINKLE mutant which accelerates the accumulation of COX- fibres. A similar, but milder, mutation (whole-body A360T) was analyzed by Tyynismaa in 2005. Since they only found modest myopathy the study appeared to weaken the mito aging theory spearheaded by Aiken-McKenzie. Accordingly, Henna Tyynismaa believes that TWINKLE mutations replicate human PEO without accelerated aging (personal communication). Similarly, many other skeptics argue that  fewer COX- cells accumulate during aging than in some mild mitochondrial diseases (e.g. Russell Hepple, personal communication).

Earlier studies suggest that COX- cells accumulate during aging and may contribute to cardiac pathology
The authors cite at least three relevant papers:
First of all "a significant part of patients with postoperative atrial fibrillation were found to suffer from mitochondrial defects in the myocardium (Montaigne et al., 2013)"

Two other papers found elevated COX- fibres in the aging heart: Müller-Höcker, 1989 and Khrapko et al., 1999, the latter linking this to deletion accumulation.

A very small level of COX- cells causes pathology in the mouse
in 12-month-old mutants, 0.17% ± 0.12% of the cells were COXneg, and this value increased three times in 18-month-old animals to 0.56% ± 0.34%, i.e., 1 in about 200 cells...
K320E-TwinkleMyo Mice Develop Ventricular Arrhythmia with Aging [at 18mo but not 12mo]
Most other cardiac parameters were unchanged suggesting that the COX- phenotype specifically leads to arrythmias:
MRI, apoptosis, heart weight to body weight ratios, average cardiomyocyte size, “mtDNA copy number, as well as abundance and functionality of the respiratory chain complexes in heart homogenates”

The pathology is relevant
Ventricular arrhythmias are the most common cause for sudden cardiac death and cause around 20% of total deaths per year in the United States...

The mechanism appears consistent with the Aiken hypothesis previously observed in COXneg segments of skeletal muscle ( Herbst et al., 2007), mtDNA copy number was higher in mutant COXneg cells...
quantification of the total deletion loads in three different pools from COXpos and COXneg cells of 18-month-old K320E-TwinkleMyo mice by single-molecule PCR revealed percentages of 85% ± 18% of mutated mtDNA in the COXneg cells and 2.3% ± 0.6% in the COXpos cells (p < 0.05).

The finding of elevated mtDNA number is consistent with a futile compensatory effort.

An analogy to senescent cell ablation
Perhaps we should get rid of COXneg heart cells if they show aberrant behaviour? So far this strategy has been very successful for senescent cells. The main problem is that killing COXneg cells could accelerate muscle loss. It is quite possible that broken COXneg muscle fibres contribute to sarcopenia.


Cell Metab. 2015 May 5;21(5):667-77. doi: 10.1016/j.cmet.2015.04.005.Mosaic Deficiency in Mitochondrial Oxidative Metabolism Promotes Cardiac Arrhythmia during Aging. Baris OR1, Ederer S1, Neuhaus JF1, von Kleist-Retzow JC2, Wunderlich CM3, Pal M3, Wunderlich FT3, Peeva V4, Zsurka G4, Kunz WS4, Hickethier T5, Bunck AC5, Stöckigt F6, Schrickel JW6, Wiesner RJ7.

2. Cell Metab. 2015 May 5;21(5):662-3. doi: 10.1016/j.cmet.2015.04.024.Modeling the aging heart: from local respiratory defects to global rhythm disturbances. Khrapko K1, Trayanova N2, Nattel S3.

3.  McKiernan, S. H., Colman, R., Lopez, M., Beasley, T. M., Weindruch, R., & Aiken, J. M. (2009). Longitudinal analysis of early stage sarcopenia in aging rhesus monkeys. Experimental gerontology, 44(3), 170-176.