A kinetic dichotomy between mitochondrial and nuclear gene expression processes

McShane, Erik; Couvillion, Mary; Ietswaart, Robert; Prakash, Gyan; Smalec, Brendan M.; Soto, Iliana; Baxter-Koenigs, Autum R.; Choquet, Karine; Churchman, L. Stirling

doi:10.1016/j.molcel.2024.02.028

Cited by 17 publications

(1 citation statement)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the mitochondrial RNA granule factor LRPPRC undergoes selective accumulation in Clpp -KO tissues [ 41 , 54 ]. LRPPRC is known to modulate the poly(A) tail of mRNAs in mitochondria [ 115 , 116 , 117 , 118 , 119 ], and its dysfunction influences the efficiency of the RNA degradosome together with the accumulation of toxic dsRNA [ 120 ].…”

Section: Novel Evidence On Clpp and Clpx’s Functions From C...mentioning

confidence: 99%

Knockout Mouse Studies Show That Mitochondrial CLPP Peptidase and CLPX Unfoldase Act in Matrix Condensates near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production

Key,

Gispert,

Auburger

2024

Genes

View full text Add to dashboard Cite

LONP1 is the principal AAA+ unfoldase and bulk protease in the mitochondrial matrix, so its deletion causes embryonic lethality. The AAA+ unfoldase CLPX and the peptidase CLPP also act in the matrix, especially during stress periods, but their substrates are poorly defined. Mammalian CLPP deletion triggers infertility, deafness, growth retardation, and cGAS-STING-activated cytosolic innate immunity. CLPX mutations impair heme biosynthesis and heavy metal homeostasis. CLPP and CLPX are conserved from bacteria to humans, despite their secondary role in proteolysis. Based on recent proteomic–metabolomic evidence from knockout mice and patient cells, we propose that CLPP acts on phase-separated ribonucleoprotein granules and CLPX on multi-enzyme condensates as first-aid systems near the inner mitochondrial membrane. Trimming within assemblies, CLPP rescues stalled processes in mitoribosomes, mitochondrial RNA granules and nucleoids, and the D-foci-mediated degradation of toxic double-stranded mtRNA/mtDNA. Unfolding multi-enzyme condensates, CLPX maximizes PLP-dependent delta-transamination and rescues malformed nascent peptides. Overall, their actions occur in granules with multivalent or hydrophobic interactions, separated from the aqueous phase. Thus, the role of CLPXP in the matrix is compartment-selective, as other mitochondrial peptidases: MPPs at precursor import pores, m-AAA and i-AAA at either IMM face, PARL within the IMM, and OMA1/HTRA2 in the intermembrane space.

show abstract