The implication of mitochondrial DNA mutation and dysfunction in periodontal diseases : Journal of Indian Society of Periodontology

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Review Article

The implication of mitochondrial DNA mutation and dysfunction in periodontal diseases

Kannan, Balachander; Arumugam, Paramasivam

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Journal of Indian Society of Periodontology 27(2):p 126-130, Mar–Apr 2023. | DOI: 10.4103/jisp.jisp_678_21
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Periodontal disease is a prevalent inflammatory disease in the oral cavity where the complex interaction between bacteria and the host immune response leads to periodontitis. Periodontal disease is classified into chronic inflammatory and aggressive inflammatory diseases by tradition. However, the recently acknowledged classification of periodontal disease is based on the clinical presentation of the disease. Periodontal disease is primarily characterized by the destruction of connective tissue of the gingival, periodontal ligament, and alveolar bone. Periodontitis infection is caused by microorganisms such as Aggregatibacter actinomycetecomitans, Bacteroides forsythus, Campylobacter rectus, Fusobacterium nucleatum, and Porphyromonas gingivalis.[1,2] Bacterial plaque is the primary etiological agent for periodontitis, the local and systemic factors of host immune components are also involved in causing the disease. The local factors might favor the accumulation of plaque and maturation, while systemic factors might decrease the host immune response including environmental, genetic, and immunological factors. The variations in genes linked with inflammatory responses might be complicated to increase the risk of periodontitis which is recently shown.[3]

Mitochondria are internal organelles of cells, and they are a cellular powerhouse, producing adenosine triphosphate (ATP) through the electron transport chain. They have a wide range of functions in cells, including calcium (Ca2+) homeostasis regulation, orchestration of apoptosis, and differentiation.[4] An abundance of evidence shows reactive oxygen species (ROS) produced by mitochondria has a role in inflammatory signaling regulation. Mitochondria implicate the inflammatory response in multiple aspects. In general, inflammation is induced by oxidative stress to create a stressful condition that leads to tissue damage and triggers chronic inflammation. This process is predominantly organized by activating the inflammasome of NOD-, LRR- and pyrin domain 3 (NLRP3).[5] The inflammatory response is induced by the mitochondria via pattern recognition receptors, damage-associated molecular patterns, and NLRP3 inflammasome activation.[6] Several nuclear gene mutations were reported in aggressive and chronic periodontitis. The list of genetic factors linked with periodontitis is still unclear, and more research work is needed to establish the biomarkers and genetic abnormalities that might allow for the early detection, prevention, and treatment of periodontitis patients at high risk. In this review, we discuss the role of mitochondrial DNA (MT-DNA) mutation in periodontal inflammation and its association with mitochondrial dysfunction.


Mitochondria have their own MT-DNA in their genome, which encodes for thirteen proteins. They play an important function in oxidative phosphorylation and are necessary for the translation of their Mt-tRNA and Mt-rRNA. More than 250 variants of pathogenic mutations were identified in the mitochondrial genome. Experimental evidence suggests that MT-DNA damage is demonstrated more extensively than nuclear DNA damage in humans due to oxidative stress.[7] A study by Govindaraj et al. in India demonstrates that in chronic periodontitis, patients are affected by 264 Mt-DNA variations in 25 complete Mt-DNA sequences. In their study, they identified 14 novel mutations in 11 chronic periodontitis patients that were only present in tissue sample DNA and not in blood sample DNA.[8] The Mt-DNA mutation in chronic periodontitis is also associated with various diseases such as cardiomyopathy, chronic progressive external ophthalmoplegia, hearing impairment, Alzheimer’s disease, Parkinson’s disease, neurological disorders, stroke, lethal infantile mitochondrial myopathy, multiple sclerosis, leukemia, and type 2 diabetes. In the Turkish population, 5-kb Mt-DNA deletions are reported in the gingival tissue of chronic periodontitis patients. This deletion was frequently observed in chronic periodontitis patients compared to a normal group.[9] Hence, further functional research in this area might provide comprehensive knowledge about mutations in Mt-DNA associated with periodontitis, which may help to develop the specific genetic markers for Mt-DNA damage related to periodontitis.

A study in the Chinese population reported that there were 421 total variants of Mt-DNA single-nucleotide polymorphism (SNP) observed in aggressive periodontitis patients. The MT-DNA SNP 8701A, 9540T, 10400C, 10873T, 14783T, 15043G, 15301G, and 10398A were found to increase the susceptibility toward aggressive periodontitis with mitochondrial dysfunction. The reason behind this presentation could be the location of SNPs in the Mt-DNA that is crucial for oxidative phosphorylation, whose complexes are involved in the production of ATP in our human body.[10] Pallavi et al. described that Mt-DNA mutations at the NADH hydrogenase subunit 4 gene and the ATP synthase F0 subunit-6 gene are linked with many diseases, including periodontitis.[11] The polymorphisms associated with periodontitis, such as G8701A and G10398A altered the mitochondrial matrix pH and intracellular calcium dynamics, which are particularly associated with the efficiency of ATP synthesis regulation. These findings suggest mitochondrial mobility and distribution of mitochondria in the cell might be the consequences of those SNPs.[12] The mitochondrial membrane potential (MMP) maintenance is the essential property of the mitochondrial function. In various mammalian species, decreased MMP has been found in aging cells, the mt-SNP G10398A was linked with decreased MMP production.[12,13] Several types of SNP associated with periodontitis impaired cell growth and mitochondrial respiratory chain, which indicates poor reconstruction from the diseases.[10] These findings suggest variations or mutations in MT-DNA affect the functions of mitochondria, which inevitably increases the vulnerability to periodontitis. Hence targeting this, MT-DNA might help to improve treatment options for periodontitis.

In a Chinese population study, a higher alteration frequency of mtDNA D-loop was observed in patients with aggressive periodontitis compared to controls. Major base substitutions were frequently reported, alongside the nucleotide deletion and substitution in aggressive periodontitis patients’ mtDNA. Wang et al., discovered that mtDNA D-loop polymorphisms m. 16126T >C, m. 16290C >T, and m. 152 T >C were significantly higher in patients with aggressive periodontitis compared to controls.[14] Clayton demonstrated that the mitochondrial D-loop is a hot spot location for mutation and any alteration in this region of mt-DNA, can interfere with the process of replication, transcription, and translation. D-loop polymorphisms can be selectively neutral, but in combination with known mtDNA pathogenic mutations, they are responsible for increased risk of disease or the rise of severe clinical outcomes.[15] The significant degree of diversity in the variable regions, HV1, HV2, and HV3 provides a precise way to approach the pathogenic phenotypes, compared to the relatively constant mtDNA coding region.[16] Mitochondrial mutations were significantly linked to periodontal diseases and led the disease to a severe form [Figure 1]. We have listed the mitochondrial DNA mutation in periodontal disease in Table 1.

Figure 1:
Role of Mitochondria in Periodontal Infection. MMP – Mitochondrial membrane potential, Mt-DNA – Mitochondrial DNA, ROS – Reactive oxygen species
Table 1:
Mitochondrial DNA mutation/single-nucleotide polymorphism associated with periodontal diseases


A study by Govindaraj et al. revealed that 60% of chronic periodontitis patients’ mitochondria had abnormal structures. Swollen cristae and vacuolated mitochondria were observed, which is compared to a control group of mitochondria with only 10% abnormality (P > 0.001). The MMP was also 4-fold decreased in periodontitis patients compared to control. Discharge of MMP has various consequences, including apoptosis in the cells. The increased level of ROS production was also observed in chronic periodontitis by 18%, which indicates that the ROS production is increased due to the inflammation of gingival tissues.[8] The oxidative stress induced by the mitochondria leads to the consequences of ischemic injury and cell death under pathological conditions. In the case of chronic periodontitis, the gingival tissues can consume a lower level of oxygen due to stressful conditions. The increased ROS production and decreased MMP are associated with the mutation of the MT-ND5 gene (complex 1) compared to the control group. The mutations T16189C, G8115R, T1243C, and A14693G mt-DNA mutations are also linked with increased ROS production, decreased MMP, and abnormalities in mitochondrial structures.[8] Decreased MMP leads to the consequences of apoptosis in the cell, which might make the diseases more vulnerable [Figure 1].

Other causative factors responsible for mitochondrial dysfunction are, hydrogen sulfide-mediated increase in ROS production and decrease in mitochondrial inner transmembrane potential observed in human gingival epithelial cells.[17]In vitro studies employing Cobalt chloride, a hypoxia mimetic induced the disruption of MMP and caused mitochondrial dysfunction in periodontal ligament cells.[18] A similar study using hydrogen peroxide (H2O2) induces increased ROS production, decreased MMP production, and ATP production to promote mitochondrial dysfunction. In addition, H2O2 significantly enhanced mitochondrial fission by decreasing the expression of mitofusin 1 and Mitofusin 2, along with increasing the expression of dynamin-related protein 1 and mitochondrial fission 1 protein.[19] Furthermore, the decreased level of MMP and increased level of ROS production were also observed in aggressive periodontitis patients compared to the control group. MMP maintenance is critical for mitochondrial function, and decreased MMP has been reported in aging cells in several mammalian species.[20] ROS production might be influenced by the consequence of decreased ATP production. In addition, mitochondrial respiratory chain defects were observed in aggressive periodontitis patients with several mitochondrial SNPs.[10] The periodontal condition affects the mitochondria’s efficiency by the alteration of ROS production, which is also directly involved in the oxidative stress in the cell.[21] Various studies in periodontitis cells show that decreased MMP has been observed in skin fibroblasts of chronic periodontitis patients compared to the control, followed by lipopolysaccharide (LPS) treatment, and mitochondrial ROS (mtROS) production has been increased in periodontitis patients’ peripheral blood mononuclear cells.[22,23] One such study demonstrated that Aggregatibacter actinomycetemcomitans-LPS caused apoptosis in human trophoblasts via a mitochondria-dependent pathway, which may play a role in periodontitis pathogenesis.[24]

Patients with periodontitis and type 2 diabetes were shown to have a high level of mitochondrial oxidative stress production (mtROS), which led to a high risk for cardiovascular disease (CVD). The increased mtROS dysregulates the immune-inflammatory response, which was observed in periodontitis in type 2 diabetes patients.[22,25] In a randomized clinical control study, 51 patients with periodontitis and type 2 diabetes were enrolled for intensive periodontal treatment. Intensive periodontal treatment markedly decreased mtROS production, and improved endothelial function and metabolic control in patients with periodontitis and type 2 diabetes compared to standard periodontal treatment.[26] These findings were suggestive of the fact that mtROS production is linked to systemic inflammation and increased CVD risk, altering metabolic control in patients with periodontitis and type 2 diabetes. In addition, chronic periodontitis patient with 7.4kb deletion in Mt-DNA affects the ATPase6 activity.[27,28] Which plays a pivotal role in oxidative phosphorylation in the electric transport chain, Mitochondrial dysfunctions might be caused by pathogenic mitochondrial, genomic mutations, or host immune response.[27,28] This may aid in the progression of periodontal disease to a more severe form.[Figure 1] We have listed the mitochondrial dysfunction and its mechanism in periodontal disease in Table 2.

Table 2:
Mitochondrial dysfunction associated with periodontitis

The existing knowledge in the field of mitochondria and periodontitis is limited. Furthermore, functional studies, mitochondrial protein role, and pathway analysis in mitochondria and periodontitis will provide a better understanding of the pathogenic mechanisms underlying periodontitis.


Mitochondria are powerhouses of the cells that play an important role in cell functions. MT-DNA mutations or alterations induced by ROS or other host responses lead to dysregulated mitochondrial function. Although several variants have been identified in the mtDNA, only a few pathogenic mutations have been found to be associated with mitochondrial dysfunction. The dysfunctioning of mitochondria leads to chronic inflammation, which may progress into severe disease phenotypes including periodontitis. In addition, increased ROS production in patients with periodontitis and type 2 diabetes increases the risk of developing CVD at a later stage. Hence, the identification of Mt-DNA mutation and pathogenic variants might offer an early diagnostic approach to reduce the burden of inflammatory conditions that may precipitate serious disease conditions. More insight into the nuclear gene mutations that can contribute to the dysfunctioning of mitochondria is also warranted to propose the inherent relationship between altered functions of mitochondria and chronic inflammatory conditions.

Financial support and sponsorship

This work was supported by the Science and Engineering Research Board (SERB), Government of India (EMEQ/2019/000411).

Conflicts of interest

There are no conflicts of interest.


The author thanks the Saveetha Dental College and Hospital, Chennai and his family for supporting and encouraging. Sincere thanks to Dr. J. Vijayashree Priyadharsini for kind feedback and suggestion for manuscript preparation.


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Mitochondrial dysfunction; mitochondrial mutation; periodontitis; reactive oxygen species production

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