The association between EBV-induced chronic fatigue syndrome with mitochondrial dysfunction was suggested many years ago [
15]. EBV can alter mitochondrial dynamics and DNA replication [
20,
21], as well as interact with latent membrane protein 1 (LMP1) and dynamin-related protein 1 (Drp1), enhancing glycolysis [
22]. It can also induce metabolic reprogramming in monocytes, which is associated with decreased autophagy and mitochondrial biogenesis. This enhances apoptosis and reduces immune surveillance [
23]. EBV also modulates c-Myc activity and glutaminolysis and thus aerobic glycolysis and enhances the activity of glutaminase-1 (GLS-1) isoforms in mitochondria, which explains its association with cancer [
24]. This therefore raises the possibility that reactivation of the EBV serves as a second mitochondrial “whammy”, leading to a sustained inflammatory response and the classical symptoms of brain fog, tiredness and weakness. This has many similarities to cytokine induced sickness behaviour associated with other conditions, such as cancer, cancer treatment, multiple sclerosis, as well as virally-induced fatigue syndrome, where mitochondrial dysfunction could also play a role [
25]. The key here is that dysfunctional mitochondria can be a source of oxidative stress, which in turn, further compromises mitochondrial recovery due to feedback and their role in inflammatory signalling [
26]. It is thus possible that even if the cause of the first whammy, the corona virus, is cleared, this imbalance can continue for some time; the second EBV whammy, whether coincident, or caused by reactivation due to reduced immune function, would only make this worse.