ARMC10 Human

What is the basic domain structure of the ARMC10 protein?

ARMC10 contains multiple armadillo (Arm) repeat domains in its carboxy-terminal region, which form the characteristic DUF634 domain. The protein typically features up to six Arm-like repeats, each containing three α-helices rich in hydrophobic amino acids. Additionally, ARMC10 contains an N-terminal signal peptide with a potential transmembrane domain, nuclear localization signals, and putative mitochondrial targeting sequences that direct the protein to its subcellular locations .

Where is ARMC10 predominantly localized within cells?

ARMC10 demonstrates dual localization within cells. The protein preferentially localizes to both nuclei and mitochondria, with experimental evidence confirming mitochondrial targeting. When expressed in cells such as HEK293AD, ARMC10 shows a clear pattern of mitochondrial staining that can be visualized using mitochondrial markers like MitoTracker. Nuclear staining is also occasionally observed in individual cells .

How conserved is the ARMC10 protein across species?

ARMC10 shows remarkable conservation across vertebrates, particularly in mammals. For example, the ARMC10 protein in mice exhibits 98% identity with the human version, with only 5 amino acid differences. This high degree of conservation suggests common and similar roles in mammals. Even in non-mammalian vertebrates like zebrafish, ARMC10 maintains approximately 79% identity with the human protein, demonstrating its evolutionary importance .

What is the genomic organization of the ARMC10 gene?

Unlike the Armcx genes which have coding sequences contained in a single exon, the ARMC10 gene has a multi-exonic structure. It is located on the 7th chromosome in humans and shows considerable syntenic conservation among vertebrates. Sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers in the genomic context of the ARMC10 locus .

What is the evolutionary relationship between ARMC10 and the Armcx gene family?

ARMC10 is considered the ancestor gene of the Armcx gene family. The Armcx genes (Armcx1-6) evolved through retrotransposition of the ARMC10 mRNA and are located in a cluster on the X chromosome. While ARMC10 is present in all vertebrates, the Armcx genes are exclusive to eutherian mammals, suggesting a recent evolutionary development. This makes ARMC10 an interesting subject for studying gene evolution and the acquisition of new functions in higher mammals .

What experimental approaches can distinguish between ARMC10 and Armcx protein functions?

Researchers can employ several strategies:

• Gene-specific knockdown or knockout experiments using siRNA or CRISPR-Cas9

• Expression of tagged proteins (EGFP or myc tags) to visualize localization patterns

• Rescue experiments in knockout models to determine functional redundancy

• Comparative protein-protein interaction studies to identify unique binding partners

• Cross-species experiments comparing species with only ARMC10 (non-eutherian vertebrates) versus those with both ARMC10 and Armcx genes (eutherian mammals)

What methods are commonly used to study ARMC10 localization in cells?

Researchers typically use transfection of cells (e.g., HEK293AD) with cDNAs encoding full-length ARMC10 fused to fluorescent or epitope tags such as EGFP or myc. Mitochondrial co-localization can be verified using specific mitochondrial stains like MitoTracker. Immunocytochemistry with antibodies against ARMC10 and various organelle markers can further confirm the subcellular distribution. For in vivo studies, immunohistochemistry on tissue sections coupled with mitochondrial markers provides evidence of natural localization patterns .

How can researchers effectively study ARMC10's role in mitochondrial dynamics?

Researchers can employ several complementary approaches:

• Live-cell imaging of labeled mitochondria in cells with ARMC10 overexpression or knockdown

• Quantification of mitochondrial movement parameters (velocity, distance, direction) in neurons

• Analysis of mitochondrial morphology using established metrics for fusion/fission

• Co-immunoprecipitation studies to identify interactions with the mitochondrial trafficking machinery

• In vitro reconstitution of mitochondrial movement using purified components

• FRAP (Fluorescence Recovery After Photobleaching) to measure dynamics of mitochondrial proteins

What protein interaction studies are most informative for understanding ARMC10 function?

The most informative protein interaction studies include:

• Co-immunoprecipitation of ARMC10 with components of the mitochondrial trafficking machinery (KIF5, Miro1-2, Trak2)

• Proximity biotinylation approaches (BioID or APEX) to identify proteins in close proximity to ARMC10 in living cells

• Surface Plasmon Resonance to measure binding affinities with potential partners

• Yeast two-hybrid screens to identify novel interactors

• Domain mapping experiments to determine which regions of ARMC10 mediate specific interactions

• Cross-linking mass spectrometry to capture transient interactions

How does ARMC10 regulate mitochondrial trafficking in neurons?

ARMC10 regulates mitochondrial trafficking by controlling the number of moving mitochondria in neurons without affecting mitochondrial aggregation. It interacts with the KIF5/Miro1-2/Trak2 trafficking complex, which is essential for mitochondrial transport along microtubules. Changes in ARMC10 levels directly impact mitochondrial mobility, with overexpression potentially promoting trafficking and depletion reducing it. This regulation is particularly important in neurons where mitochondrial positioning at synapses and other high-energy demand sites is critical for neuronal function .

What role does ARMC10 play in neuroprotection against amyloid-beta toxicity?

ARMC10 has demonstrated protective effects against amyloid-beta (Aβ)-induced toxicity in neurons. Overexpression of ARMC10 prevents Aβ-induced mitochondrial fission and subsequent neuronal death. This suggests that ARMC10 helps maintain normal mitochondrial dynamics under cellular stress conditions, potentially by promoting fusion or inhibiting excessive fission. This protective function could have implications for neurodegenerative diseases like Alzheimer's disease where Aβ toxicity and mitochondrial dysfunction are prominent features .

How does ARMC10 function as a receptor for oncomodulin (Ocm) in axon regeneration?

Recent research has identified ARMC10 as a high-affinity receptor for oncomodulin (Ocm), a myeloid cell-derived growth factor that enables axon regeneration after nerve injury. Through this receptor function, ARMC10 is necessary for inflammation- and Ocm-mediated regeneration of axons in the optic nerve, accelerated regeneration of peripheral nerves, and regeneration of dorsal root ganglion axons in the injured spinal cord. ARMC10 is also expressed on human iPSC-derived sensory neurons where Ocm promotes neurite outgrowth, suggesting therapeutic potential for neural repair strategies .

What techniques can quantify ARMC10's effects on mitochondrial morphology and dynamics?

Researchers can employ several approaches:

• Time-lapse microscopy with labeled mitochondria to track movement in real-time

• Morphometric analysis software to quantify mitochondrial size, shape, and network parameters

• Measurement of mitochondrial fusion/fission rates using photoactivatable mitochondrial markers

• Analysis of mitochondrial membrane potential using potential-sensitive dyes

• Electron microscopy to examine ultrastructural changes in mitochondrial cristae organization

• Functional assays measuring ATP production, oxygen consumption, and respiratory capacity

What is known about ARMC10's involvement in neurodegenerative diseases?

ARMC10 has been implicated in several neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD). Its protective effect against Aβ-induced mitochondrial fission and neuronal death suggests a potential role in AD pathogenesis. Additionally, given its role in mitochondrial dynamics and trafficking, ARMC10 dysfunction could contribute to the mitochondrial abnormalities observed in various neurodegenerative conditions. The table below summarizes some disease associations of the ARMC subfamily:

Although this table includes only partial information from the search results, it highlights the connections between ARMC proteins and neurodegenerative diseases .

How is ARMC10 implicated in cancer biology?

Several members of the ARMC10/Armcx family, including ARMC10 itself, have been implicated in tumorigenesis. Some members of the ARMC family can regulate or are directly regulated by the Wnt signaling pathway, which is involved in carcinogenesis and tumor progression. The initial discovery of some Armcx genes came from studies showing their loss in various human carcinomas. Current research continues to explore how alterations in ARMC10 expression or function might contribute to cancer development or progression, possibly through effects on mitochondrial dynamics, cell death resistance, or signaling pathway modulation .

What methodological approaches can link ARMC10 dysfunction to disease mechanisms?

Researchers can employ multiple approaches:

• Analysis of ARMC10 expression levels and mutations in patient samples compared to controls

• Generation of disease-relevant cellular models with ARMC10 manipulation (overexpression/knockdown)

• Creation of transgenic animal models to study ARMC10 in disease contexts in vivo

• Pharmacological manipulation of ARMC10 or its downstream pathways in disease models

• High-throughput screening for compounds that modify ARMC10 function or expression

• Use of patient-derived iPSCs differentiated into relevant cell types to study ARMC10 in disease-specific genetic backgrounds

How do post-translational modifications regulate ARMC10 function?

Although specific information about post-translational modifications of ARMC10 is limited in the search results, this represents an important research question. Potential approaches include:

• Mass spectrometry analysis to identify phosphorylation, acetylation, ubiquitination, or other modifications

• Site-directed mutagenesis of potential modification sites to assess functional consequences

• Investigation of kinases, phosphatases, acetyltransferases, or other enzymes that might modify ARMC10

• Study of how modifications change in response to cellular stress, mitochondrial dysfunction, or disease conditions

• Analysis of how modifications affect ARMC10 localization, stability, or interactions with binding partners

What is the structural basis for ARMC10's interaction with the mitochondrial trafficking machinery?

Understanding the structural basis of ARMC10's interaction with the KIF5/Miro1-2/Trak2 trafficking complex requires:

• Determination of crystal or cryo-EM structures of ARMC10 alone and in complex with binding partners

• Domain mapping experiments to identify specific regions involved in protein-protein interactions

• Molecular dynamics simulations to predict binding interfaces and conformational changes

• Site-directed mutagenesis of predicted interface residues to validate structural models

• In vitro binding assays with purified components to measure affinity constants

• FRET or other proximity-based assays to monitor interactions in living cells

How does the nuclear localization of ARMC10 relate to its mitochondrial function?

The dual localization of ARMC10 to both mitochondria and nuclei raises intriguing questions about potential coordination between these compartments:

• What determines the balance between nuclear and mitochondrial localization?

• Does ARMC10 shuttle between compartments in response to cellular signals?

• Does nuclear ARMC10 participate in transcriptional regulation of mitochondrial genes?

• Could ARMC10 be part of a retrograde signaling pathway from mitochondria to nucleus?

• Are there distinct pools of ARMC10 with different functions based on localization?

Research approaches could include mutation of localization signals, compartment-specific tethering, and transcriptomic analysis after manipulation of ARMC10 in specific compartments .

How can ARMC10 be targeted therapeutically for neurological disorders?

Based on ARMC10's roles in mitochondrial dynamics and axon regeneration, therapeutic targeting strategies might include:

• Small molecule screening for compounds that enhance ARMC10's neuroprotective functions

• Development of gene therapy approaches to modulate ARMC10 expression in specific neuronal populations

• Design of peptide mimetics that could replicate ARMC10's interaction with oncomodulin or mitochondrial trafficking proteins

• Exploration of the ARMC10-Ocm axis as a therapeutic target for promoting neural repair

• Investigation of combinatorial approaches targeting ARMC10 alongside other regeneration-promoting factors

• Development of biomarkers for ARMC10 function to identify patients who might benefit from targeted therapies

What are the most promising experimental models for studying ARMC10 in human disease?

Several experimental models offer advantages for ARMC10 research:

• Human iPSC-derived neurons, particularly for neurodegenerative disease modeling

• Primary neuronal cultures for high-resolution imaging of mitochondrial dynamics

• Transgenic mouse models with conditional ARMC10 manipulation

• Axon injury models (optic nerve, spinal cord, peripheral nerve) to study regeneration

• Organoid cultures to examine ARMC10 function in three-dimensional tissue contexts

• CRISPR-engineered cell lines with tagged endogenous ARMC10 for physiological studies

• Cross-species comparisons between mammals with and without the Armcx gene family

How do ARMC10 and the Armcx family members cooperate or compensate for each other?

This complex question requires:

• Double or multiple knockout experiments targeting ARMC10 and various Armcx family members

• Transcriptomic and proteomic analysis to identify compensatory changes after manipulation of individual family members

• Rescue experiments determining which family members can substitute for others

• Comparative analysis of protein interaction networks for different family members

• Investigation of potential heteromeric complexes between ARMC10 and Armcx proteins

• Evolutionary analysis of functional divergence across species with different complements of family members