Mitochondrial changes associated with viral infectious diseases in the paediatric population

Abstract

Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization reports. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins into the complexes of the electron transport chain; (ii) impact on mitochondrial genome (depletion, deletions and point mutations) and mitochondrial dynamics (fusion and fission); (iii) membrane potential impairment; (iv) apoptotic regulation; and (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with considerable impact on the quality of life of the children and could even cause death. Herein, we use a systematic review to explore the association between mitochondrial alterations in paediatric infections including human immunodeficiency virus, cytomegalovirus, herpes viruses, various forms of hepatitis, adenovirus, T-cell lymphotropic virus and influenza. We analyse how these paediatric viral infectious processes may cause mitochondrial deterioration in this especially vulnerable population, with consideration for the principal aspects of research and diagnosis leading to improved disease understanding, management and surveillance.

Keywords: antivirals; infections; mitochondria; paediatrics; virus.

FIGURE 1

Mitochondrial respiratory chain and oxidative phosphorylation system, located in the inner mitochondrial membrane. Oxidative phosphorylation is the synthesis process of ATP coupled to oxygen consumption, through the transfer of electrons in stages. The electrons flow through the MRC through oxidation–reduction (or redox) reactions ending in complex IV, where oxygen is the final receptor for the electrons and is reduced to H₂O. In the OXPHOS, oxygen is consumed and an electrochemical gradient is established, driving ATP synthesis. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoQ, co‐enzyme Q; CytC, cytochrome C; e, electrons; FADH, flavin and adenine dinucleotide; H+, proton; I, I complex; II, II complex; III, III complex; IV, IV complex; MRC, mitochondrial respiratory chain; NADH, Nicotinamide adenine dinucleotide hydrogen; OXPHOS, oxidative phosphorylation system; V, V complex

FIGURE 2

Different stages of HIV infection over time. The stages are (a) acute infection (also known as primary infection), which lasts for several weeks and it can include symptoms like fever, lymphadenopathy, pharyngitis, myalgia, or mouth and esophageal sores. (b) The latency stage involves few or no symptoms and can last from 2 weeks to 20 years or more. (c) AIDS defined by low CD4⁺ T cell counts <200/μl, increased viral loads, various infections opportunists and cancers,

FIGURE 3

Site of action of the different types of antiretroviral treatment within the host cell during HIV replication. Fusion and entrance inhibitors block the fusion and entrance of the virus in the host cell. Reverse transcriptase inhibitors block the retrotranscription from viral RNA to DNA. Integrase inhibitors inhibit the integration of proviral DNA into the cell nuclear genome. Protease inhibitors block the protease enzyme and therefore the assembly of the virions. Post‐attachment inhibitors block the HIV from attaching the CCR5 and CXCR4 co‐receptors of the host cell

FIGURE 4

Mitochondria‐associated membranes or MAM: endoplasmic reticulum and mitochondrial sub‐compartments. Contact is shown with IP3R3, a Ca²⁺ signalling complex components on the ER; GRP75 on cytosol and VDAC on the outer mitochondrial membrane. Ca²⁺ efflux from ER is regulated by chaperones (BiP and Sig‐1R) as well as vMIA. ER, endoplasmic reticulum; vMIA, viral mitochondria‐localized inhibitor of apoptosis

FIGURE 5

General summary of the main mitochondrial changes associated to viral agents and antiviral drugs, described in the present review. To summarize, all viruses herein depicted are related to apoptosis and subsequent ROS production, often related to mitochondrial respiratory chain dysfunction. Specifically, HIV is able to promote metabolic changes and HIV‐infected (and bystander) cells undergo apoptosis, present imbalance between oxidants and antioxidants, and Ca²⁺ overload, as an HIV‐derived toxic effect. HCMV, which presents both anti‐ and pro‐apoptotic properties, also affects cell metabolism, and induces mitochondrial biogenesis and respiration, to facilitate its own replication, which otherwise triggers increased ROS. HSV is associated with inhibition of mitochondrial respiratory chain between CII and CIII, ROS/Ca²⁺ overload and CytC release. HV affects mito‐dynamics by promoting mitochondrial fragmentation and changes in mitochondrial morphology and mitophagy, in association with ROS generation. On the other hand, anti‐HIV/anti‐HCMV/anti‐HV NRTIs are classically associated to mtDNA depletion, due to off‐target inhibition of endogenous polymerases, whereas protease inhibitors are associated with mitochondrial network fragmentation (mito‐dynamics), apoptosis and ROS/calcium generation. Ca²⁺, calcium; CytC, cytochrome C; Mito‐dynamics: mitochondrial fusion, mitochondrial fission and mitochondrial transport; ROS, reactive oxygen species; TCA, tricarboxylic acid