MINOS1/Mio10, a conserved mitochondrial protein, is required for mitochondrial inner membrane organization and cristae morphology. MINOS1/Mio10 is a novel constituent of the mitofilin/Fcj1 complex of the inner membrane, linking the morphology phenotype of the mutant to the activity of the mitochondrial inner membrane organizing complex.
The Tim50 subunit of the mitochondrial TIM23 complex contains a presequence-binding domain that is essential for viability and precursor transport across the inner membrane.
The mitochondrial presequence translocase interacts with presequence-containing precursors at the intermembrane space (IMS) side of the inner membrane to mediate their translocation into the matrix. Little is known as too how these matrix-targeting signals activate the translocase in order to initiate precursor transport. Therefore, we analysed how signal recognition by the presequence translocase initiates reorganization among Tim-proteins during import. Our analyses revealed that the presequence receptor Tim50 interacts with Tim21 in a signal-sensitive manner in a process that involves the IMS-domain of the Tim23 channel. The signal-driven release of Tim21 from Tim50 promotes recruitment of Pam17 and thus triggers formation of the motor-associated form of the TIM23 complex required for matrix transport.
Regulation of replication and expression of mitochondrial
DNA
(mt
DNA
) is essential for cellular energy conversion via oxidative phosphorylation. The mitochondrial transcription elongation factor (
TEFM
) has been proposed to regulate the switch between transcription termination for replication primer formation and processive, near genome‐length transcription for mt
DNA
gene expression. Here, we report that
Tefm
is essential for mouse embryogenesis and that levels of promoter‐distal mitochondrial transcripts are drastically reduced in conditional
Tefm
‐knockout hearts. In contrast, the promoter‐proximal transcripts are much increased in
Tefm
knockout mice, but they mostly terminate before the region where the switch from transcription to replication occurs, and consequently,
de novo
mt
DNA
replication is profoundly reduced. Unexpectedly, deep sequencing of
RNA
from
Tefm
knockouts revealed accumulation of unprocessed transcripts in addition to defective transcription elongation. Furthermore, a proximity‐labeling (Bio
ID
) assay showed that
TEFM
interacts with multiple
RNA
processing factors. Our data demonstrate that
TEFM
acts as a general transcription elongation factor, necessary for both gene transcription and replication primer formation, and loss of
TEFM
affects
RNA
processing in mammalian mitochondria.
Pathogenic variants in
FBXL
4
cause a severe encephalopathic syndrome associated with mt
DNA
depletion and deficient oxidative phosphorylation. To gain further insight into the enigmatic pathophysiology caused by
FBXL
4 deficiency, we generated homozygous
Fbxl4
knockout mice and found that they display a predominant perinatal lethality. Surprisingly, the few surviving animals are apparently normal until the age of 8–12 months when they gradually develop signs of mitochondrial dysfunction and weight loss. One‐year‐old
Fbxl4
knockouts show a global reduction in a variety of mitochondrial proteins and mt
DNA
depletion, whereas lysosomal proteins are upregulated. Fibroblasts from patients with
FBXL
4 deficiency and human
FBXL
4
knockout cells also have reduced steady‐state levels of mitochondrial proteins that can be attributed to increased mitochondrial turnover. Inhibition of lysosomal function in these cells reverses the mitochondrial phenotype, whereas proteasomal inhibition has no effect. Taken together, the results we present here show that
FBXL
4 prevents mitochondrial removal via autophagy and that loss of
FBXL
4 leads to decreased mitochondrial content and mitochondrial disease.
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