Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

AbstractMitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.</div

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondria) one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondria! unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.Peer reviewe

Multiple injections of energetic electrons associated with the flare and CME event on 9 October 2021

Context. We study the solar energetic particle (SEP) event observed on 9 October 2021 by multiple spacecraft, including Solar Orbiter. The event was associated with an M1.6 flare, a coronal mass ejection, and a shock wave. During the event, high-energy protons and electrons were recorded by multiple instruments located within a narrow longitudinal cone. Aims. An interesting aspect of the event was the multi-stage particle energisation during the flare impulsive phase and also what appears to be a separate phase of electron acceleration detected at Solar Orbiter after the flare maximum. We aim to investigate and identify the multiple sources of energetic electron acceleration. Methods. We utilised SEP electron observations from the Energetic Particle Detector (EPD) and hard X-ray (HXR) observations from the Spectrometer/Telescope for Imaging X-rays (STIX) on board Solar Orbiter, in combination with radio observations at a broad frequency range. We focused on establishing an association between the energetic electrons and the different HXR and radio emissions associated with the multiple acceleration episodes. Results. We find that the flare was able to accelerate electrons for at least 20 min during the non-thermal phase, observed in the form of five discrete HXR pulses. We also show evidence that the shock wave contributed to the electron acceleration during and after the impulsive flare phase. The detailed analysis of EPD electron data shows that there was a time difference in the release of low- and high-energy electrons, with the high-energy release delayed. Also, the observed electron anisotropy characteristics suggest a different connectivity during the two phases of acceleration.ISSN:0004-6361ISSN:1432-074