Instituto Universitario de Biología Molecular

Role of mitochondrial metabolism on the pathophysiology of skeletal muscle

Prof. Laura Formentini. Profesora Contratada Doctor.  Departamento de Biología Molecular. UAM.

Our investigation aims at understanding how mitochondrial bioenergetics participate in the integration of different cellular functions. Complex regulatory mechanisms enable mitochondrial metabolism to match cell demands, which extend beyond the production of ATP: during the last decade we demonstrated that mitochondrial oxidative phosphorylation (OXPHOS) plays further roles in controlling cell death (EMBO J, 2014, 33(7):762-78); immunity (Cell Reports, 2017, 19(6):1202-1213) and oncogenesis (Mol Cell, 2012, 45(6):731-42; Nat Comm, 2020, 11:3606). Impaired mitochondrial function also deeply alters lipid species and metabolism (Diabetologia, 2017, 60(10):2052-2065; EMBO J. 2020, e103812) and is emerging as a pivotal hallmark of metabolic disorders. Understanding which products of metabolism are limiting for correct cell function, and how cells obtain or transform them in physiological tissue environments, is crucial to exploit mitochondrial metabolism for therapy.

The main achievement of our research over the last two years was to deepen our knowledge of mitochondrial metabolism in the pathophysiology of skeletal muscle, the highest oxidative tissue in mammals. We defined how chronic mitochondrial dysfunctions drive the formation of muscular tubular aggregates (TA), honeycomb-like arrays of sarcoplasmic reticulum (SR) tubules that induce severe sarcomere disorganization and muscular pain. TA develops in the skeletal muscle of patients with Tubular Aggregate Myopathy (TAM, ORPHA:2593; OMIM:160565, 615883) as well as in other disorders, including endocrine syndromes, diabetes, and aging, although their primary cause is unknown. We investigated the molecular mechanisms of TA onset and a potential therapy in a preclinical mouse model of the disease. We showed that upon chronic in vivo inhibition of the mitochondrial ATP synthase, oxidative soleus muscle experiments a metabolic and structural switch towards glycolytic fibers, increases mitochondrial fission, and activates mitophagy to recycle damaged mitochondria. TA results from the over-response of the fission controller DRP1, which upregulates the Store-Operate-Calcium-Entry and increases the mitochondria-SR interaction in a futile attempt to buffer calcium overloads upon prolonged OXPHOS inhibition. Accordingly, hypoxic muscles cultured ex vivo show an increase in mitochondria/SR contact sites and autophagic/mitophagic zones, where TA clusters grow around defective mitochondria. Moreover, hypoxia triggered a stronger TA formation upon ATP synthase inhibition, and this effect was reduced by the DRP1 inhibitor mDIVI. In vivo edaravone treatment in mice with restrained OXPHOS restored a healthy phenotype by prompting mitogenesis and mitochondrial fusion. Altogether, our data provide a functional link between the ATP synthase/DRP1 axis and the setting of TA, and repurpose edaravone as a possible treatment for TA-associated disorders (Cell Death Dis. 2022 Jun 22;13(6):561).

Ultimately, our investigation aims to provide knowledge based on new mitochondrial aspects for better prevention, diagnosis, and therapy of metabolic and rare diseases that target skeletal muscle.