Mitochondrial DNA and Type II Diabetes Mellitus

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1.1 Evolution of Mitochondrial DNA

Lynn Margulis. Taken at her conference at the III Congress about Scientific Vulgarization in La Coruña, Spain, on November 9, 2005. By Jpedreira - Self-published work by Jpedreira, CC BY-SA 2.5,

In 1966, Lynn Margulis wrote a paper entitled “On the Origin of Mitosing Cells”. In her paper, Margulis came up with an influential theory that has been shaping modern science ever since. Although it was hard for her to publish it in magazines, she was determined that the similarity between mitochondria and bacteria was far more meaningful than sheer coincidence.That theory is now famously known as the Endosymbiosis theory. Endosymbiosis explains the origin of eukaryotes. It is suggested that the first step in the origin of eukaryotes from prokaryotes was related to survival in the new oxygen-containing atmosphere: an aerobic prokaryotic microbe (i.e. the protomitochondrion) was ingested into the cytoplasm of a heterotrophic anaerobe. This endosymbiosis became obligate and resulted in the evolution of the first aerobic amitotic amoeboid organisms. By hypothesis, some of these amoeboids ingested certain motile prokaryotes. Eventually these, too, became symbiotic in their hosts. The association of the motile prokaryote with the amoeboid formed primitive amoeboflagellates. In these heterotrophic amoeboflagellates classical mitosis evolved. The evolution of mitosis, insuring an even distribution of large amounts of nucleic acid (i.e. host chromosomes containing host genes) at each cell division, must have taken millions of years. It most likely occurred after the transition to the oxidizing atmosphere, since all eukaryotic organisms contain mitochondria and are fundamentally aerobic. [1]

When the amoeboids ingested the prokaryotes, they also took in the genetic material of the prokaryotes. This genetic material is termed as mitochondrial DNA. A few years after the publication of the paper, scientists were able to study and sequence genomes of different species. In fact, the year 2014 saw more than a thousand new mitochondrial genome sequences deposited in GenBank—an almost 15% increase from the previous year. Hundreds of peer-reviewed articles accompanied these genomes, making mitochondrial DNAs (mtDNAs) the most sequenced and reported type of eukaryotic chromosome. [2]
A cell contains numerous mitochondria, and each mitochondrion contains dozens of copies of the mitochondrial genome. Moreover, the mitochondrial genome has a higher mutation rate (about 100-fold higher) than the nuclear genome. This leads to a heterogeneous population of mitochondrial DNA within the same cell, and even within the same mitochondrion; as a result, mitochondria are considered heteroplasmic. When a cell divides, its mitochondria are partitioned between the two daughter cells. However, the process of mitochondrial segregation occurs in a random manner and is much less organized than the highly accurate process of nuclear chromosome segregation during mitosis. As a result, daughter cells receive similar, but not identical, copies of their mitochondrial DNA.[3]

1.2 The Human Mitochondrial DNA
The human mitochondrial DNA was sequenced and the different genes and their products-RNAs and tRNAs- are under constant study. The human mitochondrial DNA (mtDNA) is a double-stranded, circular molecule of 16 569 bp and contains 37 genes coding for two rRNAs, 22 tRNAs and 13 polypeptides. The mtDNA-encoded polypeptides are all subunits of enzyme complexes of the oxidative phosphorylation system. [4]

The Human Mitochondrial DNA. Image from Jan-Willem Taanman, The mitochondrial genome: structure, transcription, translation and replication, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Volume 1410, Issue 2, 1999, Pages 103-123, ISSN 0005-2728, (

The sequence shows extreme economy in that the genes have none or only a few noncoding bases between them, and in many cases the termination codons are not coded in the DNA but are created post-transcriptionally by polyadenylation of the mRNAs.[5]
Insulin secretion by pancreatic β‐cells is critically dependent on ATP synthesis by mitochondrial oxidative phosphorylation (OXPHOS).
1.3 Type II Diabetes Mellitus
Diabetes, type 2: One of the two major types of diabetes, the type in which the beta cells of the pancreas produce insulin but the body is unable to use it effectively because the cells of the body are resistant to the action of insulin. Although this type of diabetes may not carry the same risk of death from ketoacidosis, it otherwise involves many of the same risks of complications as does type 1 diabetes (in which there is a lack of insulin).[6] Type 2 diabetes used to be known as adult-onset diabetes, but today more children are being diagnosed with the disorder, probably due to the rise in childhood obesity. There's no cure for type 2 diabetes, but losing weight, eating well and exercising can help manage the disease. If diet and exercise aren't enough to manage your blood sugar well, you may also need diabetes medications or insulin therapy.[7]

The Human Mitochondrial DNA and Type II Diabetes Mellitus

Approximately 0.5–1.5% of all diabetic patients exhibit pathogenic mtDNA defects such as duplications, point mutations and large-scale deletions. Most of the known mtDNA mutations cause diabetes by affecting insulin secretion from pancreatic beta cells. Gerbitz et al. have well illustrated the mitochondrial metabolisms in the process of glucose-induced insulin secretion in beta cells. Glucose enters the cells through a specific transporter and stimulates binding of glucokinase to the mitochondrial pore protein, porin. This is followed by phosphorylation of glucose, activation of glycolysis and stimulation of mitochondrial oxidative phosphorylation, resulting in an increase of intracellular ATP. This leads to the closure of the ATP-sensitive K+-channel, the opening of the Ca2+-channel and the increased intracellular Ca2+, which eventually triggers insulin secretion. It is thus likely that pancreatic beta cells with abnormal mitochondria would show a poor insulin secretory response to glucose stimulation. [8]
Thirteen essential OXPHOS proteins are synthesised within mitochondria from the maternally inherited mitochondrial DNA (mtDNA). This raises the possibility that a more subtle genetic variation of the mtDNA might contribute to the risk of developing the disorder by interacting with other genetic and environmental factors.[9]

Multiple studies show that mutations on the different sections of the mitochondrial DNA could be reasons for the development of type 2 diabetes. The following are a few of those many studies.
1. A gradual development of pancreatic β-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic β-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Hepatic glucose production may be another factor that becomes deregulated by the A3243G mutation. A mitochondrial dysfunction in muscle is expected to lead to a higher lactate flux to the liver, fueling gluconeogenesis. At this time, no data are available on hepatic glucose production and its suppression by insulin in carriers of the A3243G mutation.[10]
2. Variants in mitochondrial DNA (mtDNA) could be associated with type 2 diabetes because ATP plays a critical role in the production and release of insulin. Diabetes can be precipitated both by mtDNA mutations and by exposure to mitochondrial poisons. The risk of inheriting diabetes from an affected mother is greater than that from an affected father, but this is not explained by maternally inherited diabetes and/or deafness (MIDD) caused by the 3243G : C mtDNA point mutation, which accounts for less than 0.5% of cases of diabetes. A common mtDNA variant (the 16189 variant) is positively correlated with blood fasting insulin, but there are no definitive studies demonstrating that it is associated with diabetes. [11]
3. Mitochondrial DNA polymorphisms that are specifically associated to a particular group have been identified, and recent research is geared towards analyzing metadata and identifying polymorphs that contribute to genetic predisposition of type II diabetes. The T3394C and A12026G polymorphs are factors for mitochondrial diabetes in the Chinese Han population.[12]

Diagram of the thrifty genotype/phenotype and its effects in later life. From [13]

4. Malnutrition during the fetal stage and early development has been known to cause diabetes II, but the link between the two phenomena has not been established. New research is stating genomic imprinting and epigenetic changes in the mtDNA as possible links. If a fetus or an infant goes through a harsh period of malnutrition, new changes will occur in the DNA of the mitochondria. These new changes are beneficial in low food conditions, but they dispose a person to type II diabetes when food is in abundance. [14]

Type II Diabetes and Bacterial Infections

Diabetes is a case where blood sugar levels are high. High blood sugar level interferes with the body's immune system and entails lower responsiveness to infections. When glucose breaks down, dicarbonyls are formed. Dicarbonyls like methylglyoxal (MGO) and glyoxal (GO) alter the structure of human beta-defensin-2 (hBD-2) peptides, hobbling their ability to fight inflammation and infection. Thus, diabetic patients have decreased immune responses to bacteria.[15]The hyperglycemic environment also favors immune dysfunction (e.g., damage to the neutrophil function, depression of the antioxidant system, and humoral immunity), micro- and macro-angiopathies, neuropathy, decrease in the antibacterial activity of urine, gastrointestinal and urinary dysmotility, and greater number of medical interventions in these patients.[16]


Overall text length should be at least 1,000 words (before counting references), with at least 2 images. Include at least 5 references under Reference section.

Subscript: H2O
Superscript: Fe3+


  1. [Lynn Sagan, On the origin of mitosing cells, Journal of Theoretical Biology, Volume 14, Issue 3,1967,Pages 225-IN6,ISSN 0022-5193,
  2. Smith DR. The past, present and future of mitochondrial genomics: have we sequenced enough mtDNAs?. Brief Funct Genomics. 2016;15(1):47–54. doi:10.1093/bfgp/elv027
  3. Smith DR. The past, present and future of mitochondrial genomics: have we sequenced enough mtDNAs?. Brief Funct Genomics. 2016;15(1):47–54. doi:10.1093/bfgp/elv027
  4. Jan-Willem Taanman, The mitochondrial genome: structure, transcription, translation and replication, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Volume 1410, Issue 2,1999, Pages 103-123, ISSN 0005-2728,
  5. Anderson, S., Bankier, A., Barrell, B. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981) doi:10.1038/290457a0
  6. Jr. WCS. Definition of Diabetes, type 2. MedicineNet. Published January 25, 2017.
  7. Type 2 diabetes. Mayo Clinic. Published January 9, 2019.
  8. Yun Yong Lee, Kyong Soo Park, Youngmi Kim Pak, Hong Kyu Lee, The role of mitochondrial DNA in the development of type 2 diabetes caused by fetal malnutrition, The Journal of Nutritional Biochemistry, Volume 16, Issue 4, 2005, Pages 195-204, ISSN 0955-2863, (
  9. [Chinnery PF, Mowbray C, Patel SK, et al. Mitochondrial DNA haplogroups and type 2 diabetes: a study of 897 cases and 1010 controls. J Med Genet. 2007;44(6):e80. doi:10.1136/jmg.2007.048876]
  10. Maassen, J. Antonie, et al. “Mitochondrial Diabetes.” Diabetes, American Diabetes Association, 1 Feb. 2004,
  11. Poulton, Joanna, Luan, et al. Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case–control study. OUP Academic. Published June 15, 2002.
  12. Liu S-M, Zhou X, Zheng F, et al. Novel mutations found in mitochondrial diabetes in Chinese Han population. Diabetes Research and Clinical Practice. Published November 27, 2006.
  13. Lee YY, Park KS, Pak YK, Lee HK. The role of mitochondrial DNA in the development of type 2 diabetes caused by fetal malnutrition. The Journal of Nutritional Biochemistry. Published April 1, 2005.
  14. Lee YY, Park KS, Pak YK, Lee HK. The role of mitochondrial DNA in the development of type 2 diabetes caused by fetal malnutrition. The Journal of Nutritional Biochemistry. Published April 1, 2005.
  15. High blood sugar of diabetes can cause immune system malfunction, triggering infection. ScienceDaily. Published August 6, 2015.
  16. Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab. 2012;16 Suppl 1(Suppl1):S27–S36. doi:10.4103/2230-8210.94253

Edited by [Beimnet Beyene Kassaye], student of Joan Slonczewski for BIOL 116 Information in Living Systems, 2019, Kenyon College.