UllrichcongenitalmusculardystrophyandBethlemmyopathyarecausedbymutationsincollagenVI(ColVI)genes,whichencodeanextracellularmatrixprotein;yet,mitochondriaplayamajorroleindiseasepathogenesisthroughashortcircuitcausedbyinappropriateopeningofthepermeabilitytransitionpore,ahigh-conductancechannel,whichcausesashortageinATPproduction.WefindthatmelanocytesdonotproduceColVIyettheybinditatthecellsurface,suggestingthatthisproteinmayplayatrophicroleandthatitsabsencemaycauselesionssimilartothoseseeninskeletalmuscle.WeshowthatmitochondriainmelanocytesofUllrichcongenitalmusculardystrophyandBethlemmyopathypatientsdisplayincreasedsize,reducedmatrixdensity,anddisruptedcristae,findingsthatsuggestafunctionalimpairment.Inkeepingwiththishypothesis,mitochondria(i)underwentanom-alousdepolarizationafterinhibitionoftheF-ATPsynthasewitholigomycin,and(ii)displayeddecreasedrespiratoryreservecapacity.Thenon-immunosuppressivecyclophilininhibitorNIM811preventedmitochondrialdepolarizationinresponsetooligomycininmelanocytesfrombothUllrihcongenitalmusculardystrophyandBethlemmyopathypatients,andpartiallyrestoredtherespiratoryreserveofmelanocytesfromoneBethlemmyopathypatient.TheseresultsmatchourrecentfindingsonmelanocytesfrompatientsaffectedbyDuchennemusculardystrophy(Pellegrinietal.,2013),andsuggestthatskinbiopsiesmayrepresentaminimallyinvasivetooltoinvestigatemitochondrialdysfunctionandtoevaluatedrugefficacyinColI-relatedmyopathiesandpossiblyinothermusclewastingconditionslikeagingsarcopenia.
Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors / Zulian A;Tagliavini F;Rizzo E;Pellegrini C;Sardone F;Zini N;Maraldi NM;Santi S;Faldini C;Merlini L;Petronilli V;Bernardi P;Sabatelli P. - In: FRONTIERS IN AGING NEUROSCIENCE. - ISSN 1663-4365. - ELETTRONICO. - 6:(2014), pp. 1-10. [10.3389/fnagi.2014.00324]
Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors.
FALDINI, CESARE;
2014
Abstract
UllrichcongenitalmusculardystrophyandBethlemmyopathyarecausedbymutationsincollagenVI(ColVI)genes,whichencodeanextracellularmatrixprotein;yet,mitochondriaplayamajorroleindiseasepathogenesisthroughashortcircuitcausedbyinappropriateopeningofthepermeabilitytransitionpore,ahigh-conductancechannel,whichcausesashortageinATPproduction.WefindthatmelanocytesdonotproduceColVIyettheybinditatthecellsurface,suggestingthatthisproteinmayplayatrophicroleandthatitsabsencemaycauselesionssimilartothoseseeninskeletalmuscle.WeshowthatmitochondriainmelanocytesofUllrichcongenitalmusculardystrophyandBethlemmyopathypatientsdisplayincreasedsize,reducedmatrixdensity,anddisruptedcristae,findingsthatsuggestafunctionalimpairment.Inkeepingwiththishypothesis,mitochondria(i)underwentanom-alousdepolarizationafterinhibitionoftheF-ATPsynthasewitholigomycin,and(ii)displayeddecreasedrespiratoryreservecapacity.Thenon-immunosuppressivecyclophilininhibitorNIM811preventedmitochondrialdepolarizationinresponsetooligomycininmelanocytesfrombothUllrihcongenitalmusculardystrophyandBethlemmyopathypatients,andpartiallyrestoredtherespiratoryreserveofmelanocytesfromoneBethlemmyopathypatient.TheseresultsmatchourrecentfindingsonmelanocytesfrompatientsaffectedbyDuchennemusculardystrophy(Pellegrinietal.,2013),andsuggestthatskinbiopsiesmayrepresentaminimallyinvasivetooltoinvestigatemitochondrialdysfunctionandtoevaluatedrugefficacyinColI-relatedmyopathiesandpossiblyinothermusclewastingconditionslikeagingsarcopenia.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
