Mitochondrial DNA Alteration in Obstructive Sleep Apnea

Donato Lacedonia; Giovanna E Carpagnano; Elisabetta Crisetti; Grazia Cotugno; Grazia P Palladino; Giulia Patricelli; Roberto Sabato; Maria P Foschino Barbaro


Respiratory Research. 2015;16(47) 

In This Article

Abstract and Introduction


Background Obstructive Sleep Apnea (OSAS) is a disease associated with the increase of cardiovascular risk and it is characterized by repeated episodes of Intermittent Hypoxia (IH) which inducing oxidative stress and systemic inflammation. Mitochondria are cell organelles involved in the respiratory that have their own DNA (MtDNA). The aim of this study was to investigate if the increase of oxidative stress in OSAS patients can induce also MtDNA alterations.

Methods 46 OSAS patients (age 59.27 ± 11.38; BMI 30.84 ± 3.64; AHI 36.63 ± 24.18) were compared with 36 control subjects (age 54.42 ± 6.63; BMI 29.06 ± 4.7; AHI 3.8 ± 1.10). In blood cells Content of MtDNA and nuclear DNA (nDNA) was measured in OSAS patients by Real Time PCR. The ratio between MtDNA/nDNA was then calculated. Presence of oxidative stress was evaluated by levels of Reactive Oxygen Metabolites (ROMs), measured by diacron reactive oxygen metabolite test (d-ROM test).

Results MtDNA/nDNA was higher in patients with OSAS than in the control group (150.94 ± 49.14 vs 128.96 ± 45.8; p = 0.04), the levels of ROMs were also higher in OSAS subjects (329.71 ± 70.17 vs 226 ± 36.76; p = 0.04) and they were positively correlated with MtDNA/nDNA (R = 0.5, p < 0.01).

Conclusions In OSAS patients there is a Mitochondrial DNA damage induced by the increase of oxidative stress. Intermittent hypoxia seems to be the main mechanism which leads to this process.


Obstructive sleep apnea syndrome (OSAS) is a disease characterized by repetitive episodes of apnea and hypopnea during sleep, inducing cyclical alterations of arterial oxygen saturation/desaturation and sleep fragmentation. Intermittent hypoxia (IH) is the major pathophysiologic character of OSAS since it is the trigger of oxidative stress, systemic inflammation, and sympathetic activation. IH also causes the increase of reactive oxygen species (ROS) production[1] and increases the expression of inflammatory cytokines through activation of NF- κB.[2,3]

Mitochondria are independent double membrane organelles found in the cytosol of eukaryotic cells which are involved in energy production, specifically they carry out oxidative phosphorylation (OXPHOS).[4] Unlike the nuclear genome, mitochondriacontain unmethylated circular DNA and composed of one heavy strand and one light strand, organized into a nucleoprotein as a complex with the transcription factor A (TFAM) protein, that is responsible of the DNA packaging into compact nucleoids, which are found associated with the inner mitochondrial membrane.[5] The lack of introns, protective histones, and the close proximity to the electron transport chain result in mithocondrial DNA (MtDNA) being more susceptible to oxidative damage than nuclear DNA (nDNA). In addition to this, mitochondria have limited DNA repair capacity.[6]

Our hypothesis is that the presence of oxidative stress can induce in OSAS patients an alteration of the transcriptional and replication machinery of mitochondrial biogenesis which would be up-regulated resulting in an increased mitochondrial biogenesis by replication of the mitochondrial genome. This change could be detected in body fluids. To test this hypothesis we used real time qPCR to measure mitochondrial to nuclear genome ratio (Mt/N) in accordance with the early theory which suggests that Mt/N is a biomarker of mitochondrial dysfunction.[7]