Mitochondrial DNA content reduction in the most fertile spermatozoa is accompanied by increased mitochondrial DNA rearrangement.
Level 4 - case-series / case-control
Observational case-control study comparing infertile men to normal controls
PubMed 35150574 · doi:10.1093/humrep/deac024
What was done
Observational comparative study of semen samples from 44 men undergoing assisted reproductive technology at a single academic center in France (20 with severe oligoasthenospermia and 24 normozoospermic controls). Spermatozoa were separated into 40% and 90% density gradient fractions. Digital PCR was used to quantify mtDNA copy number, and next-generation deep sequencing with a soft-clipping workflow was used to profile mtDNA variants and large genomic rearrangements (deletions and duplications).
What was found
Spermatozoa from the severe oligoasthenospermia group had significantly higher mtDNA copy numbers than the control group (P < 0.0001). Across both groups, mtDNA content was higher in the 40% layer than in the 90% layer (severe oligoasthenospermia: P = 0.02; controls: P < 0.0001). In contrast, the frequency of large mtDNA deletions and duplications was significantly higher in controls than in the severe oligoasthenospermia group (P = 0.002). Heteroplasmic variants were slightly more frequent in the severe oligoasthenospermia group (P = 0.05) and in the 40% layer (P = 0.03), but carried no obvious functional consequence.
Why it matters
The findings demonstrate that large mtDNA rearrangements are elevated in the most fertile sperm fractions alongside reduced mtDNA copy number. This challenges the theory that mtDNA structural alterations necessarily indicate pathological mitochondrial dysfunction or trigger compensatory mtDNA copy-number expansion.
Limits
The sample size was small (n = 44) from a single academic center. The comparison was limited to severe oligoasthenospermia versus normal semen parameters, excluding other male infertility phenotypes. Clinical outcomes such as fertilization rates, pregnancy, or live births were not measured.
Cited by
- supports Compelling scientific data links sperm mitochondrial DNA content per sperm to infertility.