The Missing Link between HAART, Mitochondrial Damage and Insulin Resistance

In this review how the highly active antiretroviral therapy (HAART) damage the mitochondria, followed by immune activation and insulin resistance. The introduction and evolution of HAART over the past 25 years have brought an amazing decrease in AIDS-and immunodeficiency-related reasons for death. However, deaths of these people are now related to metabolic disorder diseases, including atherosclerotic cardiovascular diseases, before from the viral infection itself. Insulin resistance is at the root causes of maladies of metabolic related disorder diseases. While it is notable that HAART metabolism and immune activation cross taking contribute advancement of insulin resistance and co-morbid illnesses. The molecular mechanisms of HAART metabolism and insulin resist is not completely understand. Emerging evidence that HAART how induced mitochondrial damage? and exacerbates the inflammatory response which leads to the development of insulin resistance are remain largely unresolved. The clarification and comprehension of these mechanisms will offer ascent to new classes of medications for the management of insulin resistance that will additionally improve the quality of life of HIV-infected patients..

There were roughly 36.9 million individuals living with HIV towards the end of 2017 with 1.8 million individuals recently infected in 2017 internationally. Among them 21.7 million individuals were under antiretroviral treatment, 59% of adults and 52% of children. There is no remedy for HIV disease. Notwithstanding, viable antiretroviral (ARV) medications can control the infection and help counteract transmission. New HIV positive fell by 36%, and HIV-related deaths fell by 38% with 11.4 million lives spared because of ART in a similar period 1 . Thus, HIV infection is these days considered "only" a chronic disease. There are in 20 affirmed antiretroviral drugs characterized into five groups as per the mechanisms by which they interfere with the HIV life cycle 2 . Longtime utilization of HAART has been identified with drug toxic effect that can bargain non-AIDS illnesses. A portion of these aggravations is insulin resistance followed by metabolic syndrome. This brings hypertriglyceridemia, hypercholesterolemia, hypertension, endocrine disorders, osteopenia , neurocognitive disorders, diabetes, cardiovascular disease, non-AIDS-defining cancers and lipodystrophy have been observed during therapy 3, 4, 5, 6 . Ongoing examinations likewise propose that utilization of HAART, liver disease speaks to a critical reason for morbidity and mortality in HIV-infected patients. These all complication is related to mitochondria damage induced by HAART. The following table listed FADapproved HIV medication latest update (January 2020)

HAART Mitochondrial Dysfunction
Every mammalian cell contains hundred to thousand mitochondria. The size, shape, and number of mitochondria change significantly in various cell types and more may change under various energy requests and distinctive physiological or natural conditions. The principle capacity of mitochondria is to incorporate ATP through electron transport and oxidative phosphorylation in combination with the oxidation of metabolites by a tricarboxylic acid cycle and catabolism of fatty acids by beta-oxidation. In this sense, the mitochondrion viewed as basically the fuel supplier for the most fundamental energy requests of the cells. On the other hand, mitochondria are presently perceived as being basic segments in the control of numerous key cellular processes, being the primary mediator in the inception and execution of apoptosis and important functions in the assurance of life and deaths of the mammalian cells.
Also, mitochondria are the principal intracellular source of reactive oxygen species (ROS) 7 . During the electron transport chain in the mitochondria, few electrons "spill" to cytosolic oxygen, forming the superoxide radical 8 . The electron transport complex I of the mitochondria leaks the electron and formation of superoxide. Mitochondria are not only important sources of ROS production, but also the major targets of ROS attack 9 . Many things influence the function of mitochondria for example, ageing, infection, and drugs, etc. These factors can injure the mitochondria, affecting the normal functions of the cell. Mitochondrial injury can change the normal functions of heart, nerves, muscles, pancreas, kidneys, and liver, causing many chronic diseases. Mitochondrial damage emerges from a deficient number of mitochondria, a failure to give essential substrates to mitochondria, or an impaired electron transport and ATP-synthesis components. The number and practical status of mitochondria in a cell can be changed by: fusion of partially damaged mitochondria to healthy mitochondria, which renews and improves its functional capacity the formation of new mitochondria by fission and completely damage mitochondria are degraded by mitophagy 10 . These occasions are controlled by complex cell processes that sense the damage of mitochondria 11 .

HAART and Mitochondria Damage
It is conceivable that chronic infection and inflammation and/ or adverse effect of the impacts of the drug on mitochondrial capacity would add to long-term complications in HIV-infected people. A substantial list of clinical appearances of mitochondrial toxicity has been portrayed within HAART-related adverse events, which is a noteworthy worry for the determination and longterm adherence to a specific treatment. Amid the period of monotherapy with zidovudine (ZDV), a nucleoside reverse transcriptase inhibitor (NRTI), a few patients created skeletal muscle myopathies 12 . Histological examination of their muscle, adipose tissue, heart and liver, biopsies discovered mitochondrial damage 13,14,15,16 . With the broad utilization of NRTIs, other clinical indications, for example, lactic acidosis, lipodystrophy, peripheral neuropathies, cardiomyopathies, and pancytopenia were found 17 . Inhibition of polymerase gamma (Pol-??), the enzyme involved in the replication of mtDNA, reduces the amount of mitochondrial DNA (mtDNA) content ensuing mitochondrial damage, was embroiled as the hidden system for these toxicities 18 . Reduction of mtDNA has been widely studied in various tissues of human and animal models such as placenta, fetal cord blood, heart, adipose tissue, skeletal muscle, brain and kidney 19,20,21,22,23 . Yet, amassing proof beyond the "Pol-?? speculation" have been brought up in the most recent years proposing that there are different types of mitochondrial damage both related and unrelated to mtDNA 24 . Accordingly, inhibition of mitochondrial RNA expression by NRTI has been seen in numerous cell lines 25 which may happen through mtRNA polymerase inhibition or by the confinement of the essential cofactors for mtRNA transcription. A few NRTIs likewise have a direct inhibitory effect on the function of mitochondria. In this manner, AZT inhibits the mitochondrial adenylate kinase and adenine nucleotide translocator in mitochondria 26 . AZT additionally increases oxidative stress (OS) and applies a direct inhibitory impact on the electron transport chain, resulting in reduction of OXPHOS 27 . NRTIs also initiate a noteworthy decrease in complex IV action through a specific inhibition of complex I 28 . In vivo evaluation with AZT showed a disturbed cardiac mitochondrial ultra structure, decreased expression of cytochrome b mRNA, and increased levels of oxidative stress in mitochondria. Prolonged mitochondrial ROS production has additionally been implicated to go with or even establish a different system of NRTI-initiated mitochondrial harmfulness. Additionally, protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) don't inhibit Pol-gamma, but the cause mitochondrial damage 29,30 . Hemandez et al reported that pregnant women under HAART medication showed subclinical mitochondrial damage of themselves and their newborn by reduction of mtDNA, mitochondrial protein synthesis and mitochondrial function 31 .Various studies reported that mitochondrial dysfunction in peripheral organs results in insulin insensitivity 32,33,34,35 Hence healthy mitochondria and its proper functions are very important for insulin sensitivity.

HAART and Insulin Resistance
Mitochondrial irregularities related with ART have been previously reported. Literature survey shows that HIV itself and ART influence mitochondrial work through a variety of components, incorporating direct increments in ROS, diminished ATP production, and reduced mitochondrial oxygen utilization 36,37,38,39 . Lower mitochondrial respiration is the potential mechanism for IR in people living with HIV 40 . A longitudinal investigation of insulin resistance (IR) in individuals living with HIV on recent ART regimens showed IR in 21%, which indicates a huge decline from 35-63% in IR compared to older ART regimens 41 . PIs of the HAART regimens potential components cause IR 42,43,44,45 even without the changes in body composition 46,47 . PIs strongly inhibits the insulin-depended glucose transporter Glut 4, prompting to peripheral IR and impaired glucose tolerance 48 .

Molecular Mechanism of Mitochondrial Damage and Insulin Resistance
Pattern recognition receptors (PPRs) are parts of the innate immune framework, whose primary job is detecting the tissue damage, cell stress and infection. The inflammatory reactions get started by NOD-linked receptor (NLR) family of cytoplasmic PRPs. There are 22 known human NLR family members, including NLRP3-inflammasome 49 . Inflammasomes are activated by a variety of physiological and pathogenic signals. Inflammasome activation is a basic segment of the innate immune reaction and is related to the basic clearance of pathogens or damaged cells. The,overall inflammasome activation is likewise a noteworthy driver of autoimmune and metabolic disorders which is fundamental for the understanding of this process in physiological and  50 .Latest investigations reported that mitochondria are connected with immune responses 51 and non communicable diseases 52,53,54 . At the point when mitochondria are injured, the dysfunctional mitochondria raise the level of reactive oxygen species (ROS) in cells and enhance immune response by activating NALP3 inflammasome 55,56,57 . Also, current reports suggested that different mitochondrial particles known as damageassociated molecular patterns (DAMPs) for example, mtDNA, cardiolipin, or dynamin-related protein 1 etc. can be dislocated to the exterior of mitochondria (e.g., cytosol, cell surface, or extracellular spaces) and activates the immune response. Different DAMPs can be discharged into cytosol by stressing cells undergoing autophagy or damage without obvious cell deaths. Proof has been brought forth regarding the autophagymediated release of high-mobility group protein B1 (HMGB1), ATP, and mtDNA etc 58 . DAMPs directly activate the inflammasome (Figure 1) , however, ROS initiation of NLRP3 can be done through thioredoxin (TRX). At the point when the cytoplasmic ROS are increased, the reduced TRX gets oxidized and detached from thioredoxin restricting protein (TXNIP) which binds to NLRP3 for activation 59 . NLRP3 inflammasome activation prompts the activation of caspase-1 60 . The activated caspase 1 is converting pronflammatory inactive form of cytokines interleukin-1β (IL-1β) and IL-18 to their active form 61 (Figure 1).Recently, the role of the IL-1β pathway in insulin resistance was well described 62,63,64 . With regards to the exact fundamental mechanism, an amazing number of genetic animal models presently showed the function of the inflammasome in interceding IL-1β-initiated insulin resistance 64 . IL-1β signaling pathway works not only for insulin resistance but also for defective insulin secretion. It has been accounted for the beta cell failure 65,66,67,68 since the cell itself produces IL-1β upon overload of glucose 65 . This is further supported by an earlier study showing that antagonist IL-1Ra treatment and defect in NALP3, caspase 1 or IL-1β in animal model recovered from hyperglycemia by improving both β cell insulin production and insulin sensitivity in peripheral organs 63,69 .
The utilization of HAART in the course of the last 20 years has changed death rates among people living with HIV. As we keep on utilized these medications clinically, we shall mind their multifaceted mitochondrial toxicity. Mitochondrial toxicity could represent a tremendous risk of HIV-AIDS patients taking HAART treatments for a prolonged period of time. The discovery of mitochondrial toxicity could be utilized, for example, tests of mitochondrial work (e.g. ATP content, enzyme activity ), assessment of the mitochondrial membrane potential, mitochondrial RNA levels or evaluation of mitochondrial proteins, the action of cytochrome C oxidase, estimation of mitochondrial mass and investigation of mitochondrial morphology. In any case, in the interest of a clear interpretation of HAART, mitochondrial toxicity mediated insulin resistance mechanisms need to be investigated. Studies such as these may help to obviously characterize the degree of HAART mediated mitochondrial dysfunction and development of IR, and furthermore decide how focusing on mitochondria might be beneficial for the treatment of IR in HIV patients. Figure 1. The connection between HAART medication and Mitochondrial damage, and stimulating IL-1β and IL-18-mediated inflammatory cascade.
NRTIs can also bind to mitochondrial DNA polymerase gamma, which is exclusively responsible for the replication of mitochondrial DNA (mtDNA). As to NNRTI (Non-Nucleoside-Transcriptase Inhibitor) or PI (Protease Inhibitors), evidence of the damage the mitochondria .Result damaged mitochondria triggers the inflammasome NLRP3, stimulating the IL-1β and IL-18-mediated inflammatory insulin resistance cascade.