People living with mitochondrial DNA depletion disorders, including thymidine kinase 2 deficiency (TK2d), may have significantly shorter telomeres than healthy individuals, according to research published recently in Mitochondrion that suggests telomere length could serve as a future disease biomarker.
Telomeres are the protective structures at the ends of chromosomes. Telomeres become shorter each time a cell divides; when they become too short, the cell stops dividing and can die.
The study’s findings provide insight into how these rare genetic conditions affect the body at a cellular level and may help explain why symptoms vary so widely among patients.
Mitochondrial DNA depletion disorders are a group of rare inherited diseases caused by a severe reduction in mitochondrial DNA, which is essential for energy production. These disorders often affect tissues with high energy needs, such as muscle, liver and brain, and can lead to life-threatening, multi-organ failure. TK2d is one form of mitochondrial DNA depletion disorder and primarily affects muscle, leading to progressive weakness.
This study included 16 patients, 14 males and two females, with confirmed mitochondrial DNA depletion disorders caused by pathogenic variants in POLG in eight patients, FBXL4 in four, SUCLA2 in two and SUCLG1 in two. Their ages ranged from 9 months to 47 years. None showed signs of bone marrow failure on standard blood counts. Researchers measured telomere length in several types of immune cells and compared results with age-matched healthy controls.
Read more about signs and symptoms of TK2d
“[O]ur findings suggest telomere length may have potential as a novel, quantifiable feature of mitochondrial disease biology,” explained the study’s authors.
Across all immune cell types tested, telomeres were significantly shorter in patients than in controls. The most pronounced difference was seen in granulocytes, a type of short-lived white blood cell, with a median difference of −2.80 kilobases compared with controls. In contrast, CD45RA-positive cells showed the smallest median difference of −1.00 kilobase. Exploratory analyses showed granulocytes had greater telomere shortening than lymphocytes and several other immune cell subsets.
When researchers examined genetic subgroups, patients with SUCLA2 variants had the shortest telomeres overall, with an adjusted median difference of −2.66 kilobases. This was followed by SUCLG1 at −1.80 kilobases, FBXL4 at −1.27 kilobases and POLG at −1.14 kilobases.
The pattern of telomere shortening in mitochondrial DNA depletion disorders such as TK2d differed from that seen in classic telomere biology disorders. Because mitochondrial dysfunction can increase oxidative stress and cellular wear, researchers believe it may accelerate telomere shortening in certain immune cells. Telomere length remained within the normal range in many early immune cell populations, suggesting the effect may be specific to high-turnover or energy-stressed cells.
For patients with TK2d and related disorders, these findings could eventually help doctors better monitor disease severity or response to treatment. The authors also noted that research has suggested part of the benefit from treatment with deoxythymidine and deoxycytidine could involve slowing or reversing telomere shortening, though more studies on this are needed.
Sign up here to get the latest news, perspectives, and information about TK2d sent directly to your inbox. Registration is free and only takes a minute.