5 research outputs found
Mitochondrial DNA deletions in oculopharyngeal muscolar dystrophy
No full textAbstractThe deletions in the mitochondrial DNA from skeletal muscle samples of two oculopharyngeal muscular dystrophy cases were studied using polymerase chain reaction techniques. The 4977 bp `common deletion' was present in both specimens, exceeding the corresponding values of similarly aged, healthy controls. In the two samples multiple different mitochondrial DNA deletions, some case-specific and present at quite high, although not pathogenetic levels, were observed. The results suggest that mitochondrial DNA deletions, and the `common deletion' in particular, might be a sensitive and early marker of a generalized mitochondrial suffering, due to a variety of pathological and physiological causes
Increased expression of mitochondrial transcription factor A and nuclear respiratory factor 1 in skeletal muscle from aged human subjects
No full textThe expression of two factors involved in the nuclear-mitochondrial crosstalk, namely the mitochondrial transcription factor A (TFAM) and the nuclear respiratory factor-1 (NRF-1), was studied in human skeletal muscle biopsies of young and aged subjects. Aged subjects presented a 2.6-fold and an 11-fold increase of the levels of TFAM protein and TFAM mRNA, respectively. The increased expression of TFAM was associated to the doubling of NRF-1 DNA-binding affinity and to a 6-fold increase of NRF-1 mRNA level. The upregulation of TFAM and NRF-1, in aged skeletal muscle, appears involved in the pathway leading to the age-related increase of mitochondrial DNA content
FAD synthase deficiency: a severe mitochondrial myopathy involving a secondary reduction of RFVT2 expression
No full textThe redox cofactor FAD is essential for mitochondrial
functionality: in the inner- membrane it ensures the activity of the
respiratory chain complex II and of the ETF/ETFQO system, in the
matrix the oxidation of pyruvate and other α-oxoacids as well as of
some amino acids. Matrix located FAD-dependent dehydrogenases
are also involved in β-oxidation of fatty acil-CoAs.
The last step of the metabolic pathway converting the vitamin
riboflavin (Rf) into FAD is catalyzed by FAD synthase (FADS), coded
by human FLAD1 [1]. FLAD1 variations were identified as a cause of a
severe lipid storage myopathy resembling Multiple Acyl CoA
Dehydrogenase Deficiency, named LSMFLAD (OMIM #255100).
Patients’ symptoms can sometimes favourably respond to Rf therapy.
In the frame of the structural and functional characterisation of
the different hFADS isoforms, we describe here some morphological
and biochemical alterations in patients’ fibroblasts expressing FLAD1
pathological variants. In these cells we observed an impairment of
mitochondrial bioenergetics, mainly due to reduction in the level of
succinate dehydrogenase flavoprotein subunit, accompanied by, at
least in one patient, an increase in cellular ROS and a decrease of
mtDNA content. In the same patient’s cells, increased PGC-1α and
PrxIII levels were also observed, suggesting an active response to
stress conditions. Interestingly enough, in patient’s fibroblasts we
proved a drastic reduction of the levels of both the transcripts and
the protein product of SLC52A2 gene, i.e., RFVT2, the main Rf
transporter in muscle [1]. The decreased levels of all the flavin
species in the cell extracts are, thus, explainable as due to the
impairment of Rf flux from outside. In conclusion, a proposal is made
here that RFVT2 may be the primary target of Rf-based (and possibly
alternative) therapeutic strategies against LSMFLAD.
[1] M. Tolomeo, A. Nisco, P. Leone, M. Barile, Development of
Novel Experimental Models to Study Flavoproteome Alterations in
Human Neuromuscular Diseases: The Effect of Rf Therapy,
International journal of molecular sciences, 21 (2020)
