A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy, 2023, Southwell et al.

A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy
Nneka Southwell; Guido Primiano; Viraj Nadkarni; Nabeel Attarwala; Emelie Beattie; Dawson Miller; Sumaitaah Alam; Irene Liparulo; Yevgeniya I Shurubor; Maria Lucia Valentino; Valerio Carelli; Serenella Servidei; Steven S Gross; Giovanni Manfredi; Qiuying Chen; Marilena D'Aurelio

Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders.

Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.

Link | PDF (EMBO Molecular Medicine)

 

Detailed paper looking at a primary mitochondrial myopathy (genetically determined mitochondrial OXPHOS disorder, principally affecting muscle). Investigates with a mouse analogue (COX10 -> cytochrome c-oxygenase deficiency). It's open access so just a few overview quotes. It's heavy on biochemical and metabolic detail, but the broad strokes seem very relevant to my inexpert eye.

 

We've previously noted that ME/CFS patients do not behave like genetic mitochondrial disease patients. Reading this paper, there seem to be many overlap findings, even if the magnitude of effect is different (eg muscle wasting).

I'm interested in the idea of whether there could be a spectrum in mitochondrial disease, whereby an acquired mitochondrial impairment is not taking effect universally, at gene level, but instead be more discrete, and able to vary over time and extent of involved cells/tissues

The impairment might be via an epigenetic mechanism, for example latent viral interference with key mitochondrial microRNA pathways. In the experimental mouse model they use —

 

See also Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts (2021) for related findings in ME/CFS.