Abstract
Mitochondria translate the RNAs for 13 core polypeptides of respiratory chain and ATP synthase complexes that are essential for the assembly and function of these complexes. This process occurs in close proximity to the mitochondrial inner membrane. However, the mechanisms and molecular machinery involved in mitochondrial translation are not fully understood, and defects in this process can result in severe diseases. Stomatin-like protein (SLP)-2 is a mainly mitochondrial protein that forms cardiolipin- and prohibitin-enriched microdomains in the mitochondrial inner membrane that are important for the formation of respiratory supercomplexes and their function. Given this regulatory role of SLP-2 in processes closely associated with the mitochondrial inner membrane, we hypothesized that the function of SLP-2 would have an impact on mitochondrial translation. 35S-Methionine/cysteine pulse labeling of resting or activated T cells from T cell-specific Slp-2 knockout mice showed a significant impairment in the production of several mitochondrial DNA-encoded polypeptides following T cell activation, including Cytb, COXI, COXII, COXIII, and ATP6. Measurement of mitochondrial DNA stability and mitochondrial transcription revealed that this impairment was at the post-transcriptional level. Examination of mitochondrial ribosome assembly showed that SLP-2 migrated in sucrose-density gradients similarly to the large ribosomal subunit but that its deletion at the genetic level did not affect mitochondrial ribosome assembly. Functionally, the impairment in mitochondrial translation correlated with decreased interleukin-2 production in activated T cells. Altogether, these data show that SLP-2 acts as a general regulator of mitochondrial translation.
Highlights
Mitochondria are essential for the function of most mammalian cells
We have previously shown that stomatin-like protein (SLP)-2, a mainly mitochondrial protein of the SPFH family of proteins, binds to cardiolipin and functions to form specialized membrane microdomains involving cardiolipin and prohibitins in the mitochondrial inner membrane that are important for the activities of certain respiratory chain complexes [13, 14], and the formation of respiratory chain supercomplexes [15]
Upon stimulation, Stomatin-like protein (SLP)-2-deficient T cells failed to upregulate the translation of many mitochondria-encoded polypeptides to the same extent as stimulated wild type (WT) T cells, with de novo COXI, Cytb, COXII, COXIII, and ATP6 protein levels being significantly lower than in activated WT T cells
Summary
Mitochondria are essential for the function of most mammalian cells. These organelles are vital for a host of cellular processes and are typically the chief source of cellular energy production due to their ability to perform oxidative phosphorylation (OXPHOS) [1]. Defects in the processes leading to expression of mitochondria-encoded polypeptides, including mtDNA maintenance, transcription, and translation, can result in improper assembly and function of mitochondrial respiratory chain complexes, a feature common to a heterogeneous set of severe, often fatal, mitochondrial diseases [4]. Mitochondrial ribosomes (mitoribosomes) are made of components generated from both the nuclear and mitochondrial genomes [5]. The assembly of these components is hypothesized to occur in two mitochondrial subcompartments in two steps: early in nucleoids, which are centers of mtDNA maintenance, replication and transcription; and later in RNA granules, locations where post-transcriptional RNA processing and maturation occur [6, 7]. A biochemical study showed that nearly half of mammalian mitoribosomes interact with the mitochondrial inner membrane [10], suggesting that this process is mediated in part by mitoribosome interaction with integral or membrane-bound proteins
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