Viral mitochondriopathy in COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), disrupts cellular mitochondria, leading to widespread chronic inflammation and multi-organ dysfunction. Viral proteins cause mitochondrial bioenergetic collapse, disrupt mitochondrial dynamics, and impair ionic homeostasis, while avoiding antiviral defenses, including mitochondrial antiviral signaling. These changes drive both acute COVID-19 and its longer-term effects, known as "long COVID". This review examines new findings on the mechanisms by which SARS-CoV-2 affects mitochondria and for the impact on chronic immunity, long-term health risks, and potential treatments.

Keywords: Chronic inflammation; Exacerbation; Long COVID; Mitochondria; Mitochondrial antiviral signaling pathway; SARS-CoV-2.

Fig. 1

SARS-CoV-2 genome organization, structural proteins, and replication cycle. The SARS-CoV-2 genome encodes structural [spike (S), envelope (E), membrane (M), nucleoprotein (N)], nonstructural (NSP1–16), and accessory proteins. The virus enters cells via angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) to release its RNA genome. This genome then undergoes replication, and virion assembly occurs within the endoplasmic reticulum–Golgi intermediate compartments. vRNA, viral RNA.

Fig. 2

Mitochondrial special roles, key functions, and SARS-CoV-2-induced mitochondrial disruption across different organs. Mitochondria in various organs, such as brain, lungs, heart, and liver, manifest structural and functional changes. SARS-CoV-2 can affect these organs by disrupting mitochondrial function, either directly or indirectly through inflammation and oxidative stress. ATP, adenosine triphosphate; MAVS, mitochondrial antiviral signaling; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species.

Fig. 3

Metabolic reprogramming in SARS-CoV-2 infection. Infected cells shift from oxidative phosphorylation (OXPHOS) to glycolysis, accumulate lactate, and promote lipid droplet formation. This process supports viral replication and induces inflammatory mediator production. Acetyl-CoA, Acetyl-coenzyme A; ADP, adenosine diphosphate; ATP, adenosine triphosphate; FAS, fatty acid synthase; G-6-P, Glucose 6-phosphate; Glu, glucose; HIF-1α, Hypoxia-inducible factor 1-alpha; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; L-LDH, l-lactate dehydrogenase; MAL, Malic acid; MDH, malate dehydrogenase; NAD+, Nicotinamide adenine dinucleotide (oxidized form); NADH, Nicotinamide adenine dinucleotide (reduced form); NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); NADP⁺, nicotinamide adenine dinucleotide phosphate (oxidized form); OAA, Oxaloacetic acid; PC, phosphocreatine; PPP, pentose phosphate pathway; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Fig. 4

Mitochondrial antiviral signaling and viral evasion mechanisms. Mitochondrial antiviral signaling (MAVS) provides an antiviral defence system with the assistance of RIG-I, MDA5, and LGP2 receptors. When the viral genome triggers conformational changes in RIG-I and MDA5 in the outer mitochondrial membrane, these receptors use their CARD domains to interact with MAVS. This interaction prompts the MAVS proteins to aggregate into MAVS signalosomes, which activates TANK-binding kinase (TBK1) and IRFs. TRAF3 and TRAF6 contribute to antiviral protection by activating NF-κB and IRF. Nuclear translocation of NF-κB initiates pro-inflammatory cytokine gene expression, whereas IRF translocation enhances interferon production. SARS-CoV-2 counteracts this defense through several mechanisms. Its ORF-9b protein inhibits RIG-I, MDA5, MAVS, and TBK1, thereby blocking IRF signaling and interferon activation. Viral membrane proteins downregulate MAVS-related pathways and restrict TRAF3, TBK1, and IRF3 recruitment to the MAVS complex. Additionally, ORF-6 blocks interferon induction by MDA5, MAVS, and TBK1. ACE2, Angiotensin-converting enzyme 2; AT-II, Angiotensin type 2 receptor; CARD, Caspase-recruitment domain; CTD, Carboxy-terminal domain; CXCL10, C-X-C motif chemokine ligand 10; ER, Endoplasmic reticulum; ICAM1, Intercellular adhesion molecule 1; IFN, Interferon; IKBα, Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; IKKα, Inhibitor of NF-κB Kinase α; IL, Interleukin; IRF, Interferon regulatory factor; ISRE, Interferon-stimulated response element; K63 poly-Ub, K63-linked ubiquitination; LGP2, Laboratory of genetics and physiology 2; M, Membrane protein; MAM, Mitochondria-associated membranes; MDA5, Melanoma differentiation-associated protein 5; MFN, Mitofusin; N, Nucleocapsid protein; NEMO, NF-κB essential modulator; NF-κB, Nuclear factor kappa B; NSP, Non-structural proteins; PHB, Prohibitin; RIG-I, Retinoic acid-inducible gene I; TBK1, TANK-binding kinase 1; TNF, Tumor necrosis factor; ORF, Open reading frame; TRAF, TNF receptor-associated factor; VCAM1, Vascular cell adhesion protein 1; VEGF, Vascular endothelial growth factor; vRNA, Viral RNA.