Abstract
Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components—in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions.
Highlights
Introduction iationsMitochondria are cytoplasmic double-membrane organelles residing within eukaryotic cells
Both mutated and wild-type mitochondrial DNA (mtDNA) allele variants can co-exist in the same individual, a condition referred to as heteroplasmy, which explains the wide spectrum of disease severity [20]
Aging is associated with reduced ER-mitochondria contact sites, having a negative impact on mitochondrial dynamics and several other processes regulated by the two organelles [104]
Summary
The transcription of mtDNA guides the synthesis of a subset of hydrophobic ETC complex subunits through mtDNA-encoded ribosomes (12S and 16S) and 22 tRNAs [14]. Harbors both the heavy- (HSP) and the light-strand promoter (LSP) of mtDNA transcription, along with the origin of heavy-strand replication (OH) and conserved cis-acting elements. The strand that generated follows aby replicative asymmetric mode.forThe termination of of transcription transcripts the LSP are used as primers replication the leading and/or specific. DNA synthesis, the enzyme activity becomes stalled or terminated approxipolymerase γ (Pol γ) generates the 3 end of this mtDNA strand. A major replication starter is the origin of light-strand replication (OL),A replication, which requires priming of the lagging strand at multiple mtDNA sites. Other modes of mtDNA have been described and involve a “bootRNA–DNA hybrids originate and replication persist as intermediates of mtDNA synthesis. Figure light-strandpromoter; promoter;OH, OH,origin originofofheavy-strand heavy-strandreplication; replication;OL, OL,origin originofoflight-strand light-strandreplication; replication; light-strand ss-DNA,single-stranded single-strandedDNA
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