Impaired energy metabolism
In his recent review with Dr. Lipkin
, Dr. Komaroff also highlighted the findings of impaired energy metabolism. "ME/CFS is characterized by a generalized impairment in energy production, a general hypo-metabolic state, and [oxidative stress] that may contribute to the pathogenesis of fatigue."
Since recent hypotheses have considered the possibility that mitochondrial dysfunction might be behind the impaired energy metabolism, we asked him about any recent advances in our understanding of mitochondrial dysfunction.
"There’s increasing evidence of impairment in producing energy molecules (ATP) from all of the necessary sources: oxygen, glucose, fatty acids and amino acids. But as to what is causing this impaired energy production, that remains obscure," he responded.
If the impaired energy metabolism is not due to mitochondrial dysfunction, what else might be behind it?
Findings from recent studies of metabolomics
(the study of all the molecules in the body that are involved in cellular nutrition) may provide some clues.
"[Metabolomics] studies have found evidence of [...] a general hypo-metabolic state characterized by depressed levels of most [cellular nutrients and by-products,]" Dr. Komaroff highlighted in the recent review.
If low levels of cellular nutrients are indeed behind the impaired energy production, then what's behind the low levels of cellular nutrients?
One possibility is oxidative stress
— a cellular condition where nutrients might become depleted by the chemical process of oxidation. Specifically, the review notes that studies have found "increased levels of pro-oxidants [...] correlating with severity of symptoms" and "decreased levels of anti-oxidants [...] that correlate with severity of symptoms."
In addition, "brain magnetic resonance imaging (MRI) has shown elevated levels of ventricular lactic acid consistent with oxidative stress."
So if oxidative stress can degrade cellular nutrients, resulting in impaired energy metabolism, then what
is behind the oxidative stress itself?
In the field of medicine, the usual suspect in oxidative stress is chronic inflammation. "The [oxidative stress] that is a central feature of ME/CFS may be a marker for [...] inflammation in response to infection or injury," the review noted.
However, Dr. Komaroff and Dr. Lipkin emphasized in the review that the sequence of events is far from clear:
"In addition to defining individual components in the pathogenesis of ME/CFS — chronic inflammation, [oxidative stress], defective energy metabolism — we also need to understand how these components interact. Several are bidirectionally related. For example, inflammation can create [oxidative stress] that, in turn, can damage mitochondrial DNA and membranes. Conversely, mitochondrial dysfunction can generate inflammation, as can [oxidative stress] sufficient to damage tissue."
—Dr. Anthony Komaroff and Dr. Ian Lipkin