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Page 170 Sulaiman et al. J Transl Genet Genom 2020;4:159-87 I https://doi.org/10.20517/jtgg.2020.27

Mitochondrial dynamics maintenance is important to preserve mitochondrial shapes, as well as its
functions, inheritance, quality control, and cellular apoptosis [119] . Inefficient mitochondrial dynamics could
lead to multifactorial diseases, including diabetes, cancer, and kidney and neurodegenerative diseases [120] .
Distinguishing whether mitochondrial dysfunction is inherited or acquired is extremely challenging and
still poorly understood [121] . Also, PMD and SMD can have overlapping phenotypes or symptoms; moreover,
some patients may not have all the components of mitochondrial disease criteria (MDC). Currently, MDC
is used to differentiate between PMD and SMD [122] . MDC uses several criteria, including energy production,
biochemical, clinical, tissue, and molecular characterizations. However, there are no universal guidelines to
diagnose mitochondrial diseases worldwide. Advances in NGS may assist in the diagnosis of PMD or SMD
accurately [123] . Comprehensive molecular profiling could determine which genes and pathways are related to
PMD and SMD, thereby improving the diagnosis of PMD or SMD.

Mitochondria and diabetes
Energy production through OXPHOS process in the mitochondria may also lead to oxidative stress
conditions by increasing ROS formation in the cells. ROS may activate pro-inflammatory pathways, reduce
nitric oxide bioavailability, and could further induce diabetic endothelial dysfunction, subsequently leading
to the development of diabetes and diabetic kidney disease (DKD) [124] . Diabetes is an endocrine disorder due
to multiple factors, including genetics, impaired insulin action, obesity, inflammation, impaired autophagy,
increased oxidative stress, and mitochondrial dysfunction [124] . The relationship of diabetes with oxidative
stress and mitochondrial dysfunction can partially be explained by the damage-associated molecular pattern
(DAMPs) that could initiate inflammatory response via various pathways such as T signaling pathways by
interacting with (1) Toll-like receptors (TLRs), (2) nucleotide-binding oligomerization domain (NOD)-like
receptor family pyrin domain containing 3 (NLRP3) inflammasome, and (3) cytosolic cyclic GMP-AMP
synthase (cGAS)-stimulator of interferon genes (STING) DNA-sensing system [120] . Interestingly, Li and
Thr,
colleagues have identified that m.15897G>A mutation of tRNA which belongs to the haplogroup D4b1, is
present in Type 2 diabetes Chinese patients, and this mutation was maternally inherited [125] . The functional
Thr
study of this mutation showed that a decreased efficiency of mitochondrial tRNA leads to reduced
efficiency of OXPHOS protein synthesis and assembly and ATP synthesis, and decreased mitochondrial
membrane potential (MMP) [125] .

Insulin resistance (IR) is one of the main risk factors for type 2 diabetes, and mitochondrial dysfunction
is related to IR development. Recent in vivo and ex vivo metabolic studies involving humans and rodents
showed that mitochondrial dysfunction could lead to ectopic lipid deposition and IR [126] . Pereira and
colleagues showed that mtDNA could activate the NLRP3 inflammasome, which subsequently causes
endothelial dysfunction and inflammation in diabetes. Diabetes reduces endothelium-dependent
vasodilation and escalates vascular ROS generation and caspase-1 and IL-1β activation in streptozotocin
-/-
(STZ)-induced diabetic C57BL/6 mice, but not in those Nlrp3 . Deficiency in NLRP3 could prevent
diabetes-associated vascular inflammatory damage and endothelial dysfunction [127] . Another example of how
mitochondrial dysfunction is associated with diabetes is via the action of the anti-diabetic drug metformin
(MF). The protective effect of MF on regulatory networks and integrated stress responses was observed in the
brain tissue of STZ-induced diabetic mice. STZ-induced diabetic mice treated with MF (20 mg/kg) showed
a significant decrease in protein carbonylation and oxidation. MF treatment also improved mitochondrial
function via the increase of the chaperone proteins (HSP60, HSP70, and LonP1) [128] . However, the exact
mechanisms of how mtDNA causes diabetes are still not fully understood.

Mitochondria and cardiovascular diseases
[3]
The role of mtDNA mutations in cardiovascular diseases (CVD) has been discussed extensively . The
MtDNA control region is important for controlling mtDNA gene expression. Umbria and colleagues studied
mutations in the mtDNA control region in 154 stroke cases and 211 myocardial infarction (MI) patients [129] .