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

[SNT Gatchaman]

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)

 

[SNT Gatchaman]

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.

Genetically defined disorders which lead to OXPHOS defects and predominantly affect skeletal muscle are defined as primary mitochondrial myopathies (PMM). Symptoms of PMM can range from relatively non-specific exercise intolerance or exercise-induced symptoms, to muscle weakness and wasting. No proven effective treatments or cures are available for PMM and clinical trials lack consensus on metabolic outcome measures. This is largely due to a limited understanding of the metabolic consequences of OXPHOS deficiency in skeletal muscle.

Metabolite dyshomeostasis has been extensively reported in mitochondrial patients. Notably, increased levels of lactic acid and tricarboxylic acid (TCA) cycle intermediates are frequently found in the blood, urine, cerebrospinal fluid, and tissues of patients with OXPHOS deficiencies. In these patients, metabolic acidosis often results in irreversible coma and eventual death.

Amino- and fatty acid metabolism is also severely affected in mitochondrial diseases. For example, elevated plasma alanine is considered a biomarker of mitochondrial disease.

despite this evidence of altered amino- and fatty acid metabolism underlying the systemic organic acid dyshomeostasis of mitochondrial patients, the biochemical mechanisms and pathogenic significance of these alterations remain incompletely defined.

 

[SNT Gatchaman]

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 —

In this mouse, genetic excision of the assembly factor heme A:farnesyltransferase (COX10) occurs selectively in skeletal muscle at birth, resulting in muscle COX (cytochrome-c oxidase) deficiency throughout the mouse lifespan, confirmed by stable depletion of COX subunits encoded by mtDNA and by nuclear DNA (COXI and COX4, respectively) and complete loss of fully assembled COX.

 

[SNT Gatchaman]

The mitochondrial integrated stress response (ISRmt) is an elaborate signaling pathway activated in mammalian cells in response to mitochondrial damage and dysfunction to preserve metabolic homeostasis

both in mouse models and human mitochondrial myopathy, the ISRmt has been associated with profound metabolic rewiring. Adaptive metabolic changes occur not only in muscle but also systemically via secretion of signaling myokines such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15).

Impaired fatty acid oxidation in OXPHOS defective muscle results in lipid accumulation

Further impacting fatty acid metabolism, we found highly elevated protein levels of the mitochondrial Acyl-CoA thioesterase 2 (ACOT2)

upregulation of ACOTs, which catalyze the hydrolysis of acyl-CoA esters to free fatty acids and CoA, mitigates mitochondrial fatty acid overload and prevents CoA limitation during incomplete fatty acid oxidation. Thus, increased levels of ACOTs further confirm that b-oxidation is impaired in COX10 KO muscle. After CoA removal, free fatty acids and fatty acid oxidation intermediates are transported out of the mitochondria as acyl carnitines and then released into circulation.

Although mitochondrial dysfunction is associated with ISRmt , the underlying triggers remain uncertain. Tracing ISR mt mechanisms in vivo can be challenging not only because of ISR tissue specificity and dependency on the severity of mitochondrial dysfunction but also because dyshomeostasis driving ISR can be rapidly cleared through tissue rewiring and interorgan exchange.

In conclusion, our results indicate that mouse and human skeletal muscle subjected to chronic OXPHOS defects implement similar patterns of energy and redox pathway rewiring at the expense of metabolic homeostasis. Metabolic dyshomeostasis, resulting in a buildup of amino acids, fatty acids, and ketone bodies

The muscle metabolic adaptations are part of inter-organ crosstalk coordinated by autocrine and endocrine effects of myokines and hormones, which take place in distinct phases. First, OXPHOS defects result in activation of the ISRmt (mitochondrial Integrated Stress Response) with increased FGF21 synthesis, secretion, and induction of ATF4 (Activating Transcription Factor 4). This is followed by a second phase, when an increased translation of specific metabolic enzymes involved in maintaining muscle energy homeostasis occurs in parallel to the inhibition of mTORC1 and protein synthesis. During this phase, FGF21 signals to liver and WAT, affecting lipolysis and leptin metabolism. In the third phase, low leptin signaling activates the HPA axis, inducing hypercorticosteronemia, which acts synergistically with FGF21 to cause adipose stores depletion and muscle lipid accumulation.

 

[SNT Gatchaman]

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