3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.

• Keywords
• 3‐methylglutaconic aciduria, YME1L1, inherited metabolic disorders, mitochondrial disorders, mitochondrial dysfunction, mitochondrial fragmentation,
• MeSH
• Child MeSH
• Fibroblasts metabolism   MeSH
• Glutarates MeSH
• Humans MeSH
• Metalloendopeptidases * genetics   metabolism   MeSH
• Mutation, Missense MeSH
• Mitochondrial Dynamics MeSH
• Mitochondrial Proteins * genetics   MeSH
• Mitochondria metabolism   MeSH
• Hearing Loss, Sensorineural genetics   MeSH
• Siblings MeSH
• Metabolism, Inborn Errors * genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• 3-methylglutaconic acid MeSH Browser
• Glutarates MeSH
• Metalloendopeptidases * MeSH
• Mitochondrial Proteins * MeSH

Mitochondrial protein quality control is crucial for the maintenance of correct mitochondrial homeostasis. It is ensured by several specific mitochondrial proteases located across the various mitochondrial subcompartments. Here, we focused on characterization of functional overlap and cooperativity of proteolytic subunits AFG3L2 (AFG3 Like Matrix AAA Peptidase Subunit 2) and YME1L (YME1 like ATPase) of mitochondrial inner membrane AAA (ATPases Associated with diverse cellular Activities) complexes in the maintenance of mitochondrial structure and respiratory chain integrity. We demonstrate that loss of AFG3L2 and YME1L, both alone and in combination, results in diminished cell proliferation, fragmentation of mitochondrial reticulum, altered cristae morphogenesis, and defective respiratory chain biogenesis. The double AFG3L2/YME1L knockdown cells showed marked upregulation of OPA1 protein forms, with the most prominent increase in short OPA1 (optic atrophy 1). Loss of either protease led to marked elevation in OMA1 (OMA1 zinc metallopeptidase) (60 kDa) and severe reduction in the SPG7 (paraplegin) subunit of the m-AAA complex. Loss of the YME1L subunit led to an increased Drp1 level in mitochondrial fractions. While loss of YME1L impaired biogenesis and function of complex I, knockdown of AFG3L2 mainly affected the assembly and function of complex IV. Our results suggest cooperative and partly redundant functions of AFG3L2 and YME1L in the maintenance of mitochondrial structure and respiratory chain biogenesis and stress the importance of correct proteostasis for mitochondrial integrity.

• Keywords
• AAA complex, AFG3L2, YME1L, mitochondria, protease,
• MeSH
• ATPases Associated with Diverse Cellular Activities genetics   metabolism   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Metalloendopeptidases genetics   metabolism   MeSH
• Mitochondrial Membranes metabolism   MeSH
• Mitochondrial Proteins genetics   metabolism   MeSH
• Mitochondria metabolism   ultrastructure   MeSH
• Cell Proliferation genetics   physiology   MeSH
• ATP-Dependent Proteases genetics   metabolism   MeSH
• Microscopy, Electron, Transmission MeSH
• Blotting, Western MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• AFG3L2 protein, human MeSH Browser
• ATPases Associated with Diverse Cellular Activities MeSH
• Metalloendopeptidases MeSH
• Mitochondrial Proteins MeSH
• ATP-Dependent Proteases MeSH
• YME1L1 protein, human MeSH Browser

p53 is a major cellular tumor suppressor that in addition to its nuclear, transcription-dependent activity is also known to function extranuclearly. Cellular stressors such as reactive oxygen species can promote translocation of p53 into mitochondria where it acts to protect mitochondrial genome or trigger cell death via transcription-independent manner. Here we report that the mammalian homologue of yeast mitochondrial Afg1 ATPase (LACE1) promotes translocation of p53 into mitochondria. We further show that LACE1 exhibits significant pro-apoptotic activity, which is dependent on p53, and that the protein is required for normal mitochondrial respiratory function. LACE1 physically interacts with p53 and is necessary for mitomycin c-induced translocation of p53 into mitochondria. Conversely, increased expression of LACE1 partitions p53 to mitochondria, causes reduction in nuclear p53 content and induces apoptosis. Thus, LACE1 mediates mitochondrial translocation of p53 and its transcription-independent apoptosis.

• Keywords
• LACE1, apoptosis, mitochondria, p53, translocation,
• MeSH
• Adenosine Triphosphatases metabolism   MeSH
• Apoptosis physiology   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Mitochondrial Proteins metabolism   MeSH
• Mitochondria metabolism   MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Transfection MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Triphosphatases MeSH
• AFG1L protein, human MeSH Browser
• Mitochondrial Proteins MeSH
• Tumor Suppressor Protein p53 MeSH
• TP53 protein, human MeSH Browser

The tarnished plant bug (TPB), Lygus lineolaris (Palisot de Beauvois) is a polyphagous, phytophagous insect that has emerged as a major pest of cotton, alfalfa, fruits, and vegetable crops in the eastern United States and Canada. Using its piercing-sucking mouthparts, TPB employs a "lacerate and flush" feeding strategy in which saliva injected into plant tissue degrades cell wall components and lyses cells whose contents are subsequently imbibed by the TPB. It is known that a major component of TPB saliva is the polygalacturonase enzymes that degrade the pectin in the cell walls. However, not much is known about the other components of the saliva of this important pest. In this study, we explored the salivary gland transcriptome of TPB using Illumina sequencing. After in silico conversion of RNA sequences into corresponding polypeptides, 25,767 putative proteins were discovered. Of these, 19,540 (78.83%) showed significant similarity to known proteins in the either the NCBI nr or Uniprot databases. Gene ontology (GO) terms were assigned to 7,512 proteins, and 791 proteins in the sialotranscriptome of TPB were found to collectively map to 107 Kyoto Encyclopedia of Genes and Genomes (KEGG) database pathways. A total of 3,653 Pfam domains were identified in 10,421 sialotranscriptome predicted proteins resulting in 12,814 Pfam annotations; some proteins had more than one Pfam domain. Functional annotation revealed a number of salivary gland proteins that potentially facilitate degradation of host plant tissues and mitigation of the host plant defense response. These transcripts/proteins and their potential roles in TPB establishment are described.

• MeSH
• Molecular Sequence Annotation MeSH
• Gene Ontology MeSH
• Heteroptera genetics   growth & development   metabolism   MeSH
• Genes, Insect genetics   MeSH
• Salivary Glands metabolism   MeSH
• Gene Expression Profiling * MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH