title: Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding.
abstract: Defective RNA metabolism and transport are implicated in aging and degeneration [1, 2], but the underlying mechanisms remain poorly understood. A prevalent feature of aging is mitochondrial deterioration [3]. Here, we link a novel mechanism for RNA export through nuclear envelope (NE) budding [4, 5] that requires A-type lamin, an inner nuclear membrane-associated protein, to accelerated aging observed in Drosophila LaminC (LamC) mutations. These LamC mutations were modeled after A-lamin (LMNA) mutations causing progeroid syndromes (PSs) in humans. We identified mitochondrial assembly regulatory factor (Marf), a mitochondrial fusion factor (mitofusin), as well as other transcripts required for mitochondrial integrity and function, in a screen for RNAs that exit the nucleus through NE budding. PS-modeled LamC mutations induced premature aging in adult flight muscles, including decreased levels of specific mitochondrial protein transcripts (RNA) and progressive mitochondrial degradation. PS-modeled LamC mutations also induced the accelerated appearance of other phenotypes associated with aging, including a progressive accumulation of polyubiquitin aggregates [6, 7] and myofibril disorganization [8, 9]. Consistent with these observations, the mutants had progressive jumping and flight defects. Downregulating marf alone induced the above aging defects. Nevertheless, restoring marf was insufficient for rescuing the aging phenotypes in PS-modeled LamC mutations, as other mitochondrial RNAs are affected by inhibition of NE budding. Analysis of NE budding in dominant and recessive PS-modeled LamC mutations suggests a mechanism by which abnormal lamina organization prevents the egress of these RNAs via NE budding. These studies connect defects in RNA export through NE budding to progressive loss of mitochondrial integrity and premature aging.
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Yihang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Hassinger
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Thomson
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Baojin
authors.initials: B
authors.lastname: Ding
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: James
authors.initials: J
authors.lastname: Ashley
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hassinger
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: vivian.budnik@umassmed.edu.
authors.forename: Vivian
authors.initials: V
authors.lastname: Budnik
mesh_terms: D000375:Aging; D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077278:RNA, Mitochondrial
chemical_list: D029721:Drosophila Proteins; D034904:Lamin Type A; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; C440308:lamin C; C029305:mitochondrial messenger RNA
keywords: ATP synthase; Drosophila; Marf; RNA export; aging; mitochondria; mitochondrial assembly regulatory factor; nuclear envelope budding; progeroid syndrome (PS); sarcopenia