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  • 28 May 2021 3:54 PM | Anonymous member (Administrator)

    Written by Daniella H. Hock, Department of Biochemistry and Pharmacology, Bio21 Institute, The University of Melbourne, Australia; David Thorburn, Murdoch Children’s Research Institute, Royal Children’s Hospital, Department of Paediatrics, University of Melbourne, Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Royal Children’s Hospital, Australia; David A. Stroud,  Department of Biochemistry and Pharmacology, Bio21 Institute, The University of Melbourne, Australia

    Mitochondria are central to energy metabolism, producing the vast majority of cellular ATP via the oxidative phosphorylation (OXPHOS) system, while also being involved in other important processes such as one carbon metabolism, calcium homeostasis, and Fe-S cluster biogenesis (1, 2). Mitochondria are fascinating organelles as they possess their own circular DNA (mtDNA) which encodes 13 proteins translated via their own ribosomes (mitoribosome) while the remaining proteins are translated in the cytosol and imported into the mitochondria (3).

    Mitochondrial disease is an umbrella term for a collection of rare genetic disorders where cells fail to produce enough energy for proper organ and tissue function (2, 4). Collectively, it affects at least 1 in 5,000 live births (5) with infants affected by the disease having a particularly poor prognosis. From the over 1,100 known proteins localised to the human mitochondria (6), at least 350 are encoded by genes in which mutations are known to cause mitochondrial disease (4). Mitochondrial disease displays extreme clinical and genetic heterogeneity, can develop at any stage of life, and usually affects organs with high energy demand such as brain, heart, liver and skeletal muscle (2, 4).

    Once mitochondrial disease is suspected based on clinical investigation, the search for the genetic variant starts (Fig. 1A). The current diagnostic paradigm typically involves massively parallel sequencing (MPS) approaches such as whole-exome sequencing (WES) and whole-genome sequencing (WGS). Despite these combined approaches, the diagnosis of mitochondrial disease is only achieved in 35-60% of suspected cases and often after years of investigation (7). For some unsolved cases, more than one variant of uncertain significance (VUS) is flagged following bioinformatic analysis, potentially requiring further functional validation to confirm pathogenicity e.g., spectrophotometric assays of OXPHOS enzyme activity and western blot analysis of single proteins. Alternatively a single pathogenic variant is found in a gene associated with autosomal recessive inheritance and it can be unclear if a second “cryptic variant” has been missed. More recently high throughput omic approaches, such as transcriptomics and proteomics, have begun to be integrated into investigations of variant pathogenicity (8). The ‘unbiased’ nature of these techniques also lends themselves to gene discovery in cases where no candidate VUS are identified. The integration of multi-omic approaches into the diagnosis of mitochondrial disease is thus not only decreasing the waiting time for a diagnosis but potentially allowing an earlier use of therapies, disease management and facilitating provision of information that can inform family planning decisions.

    Since 2017 we have been developing and applying quantitative proteomics approaches to undiagnosed cases of rare diseases with a focus on patients with clinically suspected mitochondrial disease, while also investigating genes that can potentially cause mitochondrial diseases (9). We have analysed a range of primary tissues, including fibroblasts from skin biopsies, lymphoblasts from blood, myoblasts, skeletal muscle and heart biopsies, and have tested different quantitative approaches to individually address each clinical case. At its most basic, we have applied label free quantitative analysis of proteome changes in whole patient material relative to a panel (usually 3-5) of controls (Fig. 1B). We have also employed fractionation of peptides for increased proteome depth, pulse labelling with stable isotopes to monitor mtDNA translation, isobaric labelling, and other approaches. Our efforts have supported the published (10-13) and unpublished diagnosis of over 30 patients, many of whom were undiagnosed for decades after extensive investigation, thus demonstrating that quantitative proteomics is a technique capable of providing evidence to support disease causation arising from various types of variants, including deep intronic variants, splice site variants, copy number variants, and missense variants present in either mitochondrial or nuclear DNA.

    The first cold case we would like to share had been undiagnosed for over 10 years, despite inconclusive results after extensive investigations which included [i] chromosomal microarray and breakage analysis, [ii] quad (both parents and affected siblings) whole exome sequencing, [iii] common mitochondrial DNA point mutations, [iv] and the gold-standard quad whole genome sequencing (11). Transcriptomic analysis (RNA sequencing) was performed and identified a reduction in NDUFB10 expression as well as novel splicing events, including the presence of a cryptic exon in NDUFB10 transcripts (Fig. 1C). We performed label free quantitative proteomics on skin fibroblasts from the patient and three control individuals. NDUFB10 peptides were actually not detected in control or patient cells but we confirmed the reduction in over twenty NDUFB10 partner proteins in patient cells, similar to the protein signature observed in knockout NDUFB10 cells (14). These proteins, along with NDUFB10 are subunits of the first complex in the mitochondrial respiratory chain, also called Complex I or NADH ubiquinone oxidoreductase. The abundance of subunits in the other complexes of the OXPHOS system were unaffected. Reanalysis of WGS data confirmed the presence of a novel deep intronic cryptic splicing variant in NDUFB10, found in homozygosity in the affected siblings and in heterozygosity in the parents.

    The second investigation involves the diagnosis of 17 patients where inherited deletions and de novo duplication had occurred in the repetitive ATAD3 locus. Mutations in this locus are now known to be one of the five most common causes of paediatric nuclear-encoded mitochondrial disease (12). The ATAD3 locus is comprised of three highly homologous genes in tandem: ATAD3C, ATAD3B and ATAD3A, an arrangement which is exclusive to hominids. The homology of the region makes it prone to nonallelic homologous recombination (NAHR) events, giving rise to copy number variations (CNVs) such as deletions and duplications. Identification of deletions and duplications events in highly homologous genomic regions can be a challenge as these regions can be refractory to the short read sequencing approaches used in WES and WGS methodologies. To overcome this problem, short read approaches were combined with long-read sequencing, transcriptomics and quantitative proteomics analyses to identify recessive biallelic deletions and dominant de novo duplications in the ATAD3 locus (Fig.1D). At the protein level, the recessive biallelic deletions give rise to a fused ATAD3B/ATAD3A protein, while the dominant de novo duplication give rise to a chimeric ATAD3A/ATAD3C protein.

    Quantitative proteomics was shown to provide valuable functional data that can add to the body of evidence needed to confirm pathogenicity of VUS in rare and long-term undiagnosed cases. Our current efforts are now focused on developing a high throughput and robust quantitative proteomics pipeline to be incorporated into routine clinical investigations of patients with suspected but undiagnosed rare disease in order to decrease the current diagnostic gap.

    Figure 1A. Example pipeline for investigation of clinically suspected rare disease. Genomic sequencing is the first line approach followed by functional validation of variants of uncertain significance (VUS) using e.g. enzymology, western blot, transcriptomics and proteomics. B. General schematic depicting workflow for functional validation of VUS via quantitative proteomics. C. Multi-omic investigation used to identify a deep intronic variant in NDUFB10, a structural subunit of mitochondrial Complex I (CI). Transcriptomic analysis identified a cryptic exon inserted between exon 1 and exon 2 of NDUFB10. Proteomics on the patient skin fibroblasts show an isolated decrease in CI. Differential protein abundances were topographically mapped to the CI structure (PDB ID: 5LDW) for visualization of the impact of mutation. Data plotted from supplemental material in (11). D. Pathogenic genetic arrangements in the ATAD3 locus identified in patients with a large deletion or duplication in the repetitive ATAD3 locus. Deep peptide fractionation and label free quantitative proteomics of patient skin fibroblasts revealed the corresponding decrease and increase in peptide abundance. Data plotted from supplemental material in (12).


    1. Jackson TD, Hock DH, Fujihara KM, Palmer CS, Frazier AE, Low YC, et al. The TIM22 complex mediates the import of sideroflexins and is required for efficient mitochondrial one-carbon metabolism. Mol Biol Cell. 2021;32(6):475-91.

    2. Frazier AE, Thorburn DR, Compton AG. Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology. J Biol Chem. 2019;294(14):5386-95.

    3. Kang Y, Fielden LF, Stojanovski D. Mitochondrial protein transport in health and disease. Semin Cell Dev Biol. 2018;76:142-53.

    4. Hock DH, Robinson DRL, Stroud DA. Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome. Biochem J. 2020;477(21):4085-132.

    5. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain. 2003;126(Pt 8):1905-12.

    6. Rath S, Sharma R, Gupta R, Ast T, Chan C, Durham TJ, et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 2021;49(D1):D1541-D7.

    7. Stenton SL, Prokisch H. Genetics of mitochondrial diseases: Identifying mutations to help diagnosis. EBioMedicine. 2020;56:102784.

    8. Alston CL, Stenton SL, Hudson G, Prokisch H, Taylor RW. The genetics of mitochondrial disease: dissecting mitochondrial pathology using multi-omic pipelines. J Pathol. 2021.

    9. Hock DH, Reljic B, Ang CS, Muellner-Wong L, Mountford HS, Compton AG, et al. HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV. Mol Cell Proteomics. 2020.

    10. Lake NJ, Webb BD, Stroud DA, Richman TR, Ruzzenente B, Compton AG, et al. Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome. Am J Hum Genet. 2017;101(2):239-54.

    11. Helman G, Compton AG, Hock DH, Walkiewicz M, Brett GR, Pais L, et al. Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10. Hum Mutat. 2021;42(1):19-24.

    12. Frazier AE, Compton AG, Kishita Y, Hock DH, Welch AE, Amarasekera SSC, et al. Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus. Med (N Y). 2021;2(1):49-73.

    13. Van Bergen NJ, Ahmed SM, Collins F, Cowley M, Vetro A, Dale RC, et al. Mutations in the exocyst component EXOC2 cause severe defects in human brain development. J Exp Med. 2020;217(10).

    14. Stroud DA, Surgenor EE, Formosa LE, Reljic B, Frazier AE, Dibley MG, et al. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature. 2016;538(7623):123-6.


    Daniella Hock is a PhD candidate in Dr David Stroud’s lab at the University of Melbourne in Australia, where she has been developing and applying quantitative proteomics approaches to improve the diagnostic rates of rare diseases, particularly paediatric mitochondrial disease. She is also interested in investigating the molecular function of genes implicated in mitochondrial disease pathogenesis with a view toward expanding the list of genes that can potentially cause mitochondrial disease. Prior to commencing her PhD, Daniella graduated as Bachelor of Biological Sciences from Universidade Federal de Santa Catarina in Brazil and worked as molecular diagnostic scientist at Biogenetika, a personalised medicine centre, in Brazil.

  • 28 May 2021 3:48 PM | Anonymous member (Administrator)

    Written by Aleksandra Nita-Lazar, National Insitute of Allergy and Infectious Diseases, USA

    The diversity concept is being widely applied and more and more often globally recognized – and HUPO is no exception. For a long time, HUPO has been committed to the principles of diversity, and this commitment is reflected in our membership and leadership. Welcoming differences, equal opportunity, diversity, and inclusion is not only a matter of civility, but a real benefit for any creative effort. Diversity has been long known as a biological force driving functional ecosystems, and genetic diversity in any population ensures biological success. More recently, diversity has been recognized and published in numerous reports and books reviewing the relevant research (to name a few excellent examples: ”Creativity and Problem Solving” by Scott Page; “Accuracy in Decision-making” by Katherine Phillips” and “Willful Blindness” and other books by Margaret Heffernan), demonstrating that any diverse group will always do better than a uniform one, bringing unique perspectives and abilities, fostering discovery, boosting innovation and preventing decision bias. Each individual brings unique capabilities, experiences, and characteristics, their own vision, igniting creativity and fueling resourcefulness. To gain access to the best ideas we need to create an environment where people feel supported, heard, and free to achieve their best and contribute to their full potential. The synergy of diverse teams is real.

    At HUPO we are connected by a common interest in all aspects of proteome research; bringing our individual experiences will strengthen the organization further, so we intentionally cultivate diversity and inclusion. The members of HUPO represent scientists from all regions and levels – we have 48% student and Postdoc members and 38% of HUPO members are women. All the active members are eligible for election to the HUPO Council. The Nominations and Elections Committee (NEC) monitors and approves the nomination and election process. Two years ago, the requirement of 10 or more years of professional experience for eligibility was waived and now trainees and junior scientists are eligible and encouraged to be nominated. To promote diversity and reduce the dominance of well-known senior scientists in HUPO elections, each of the three regions (Eastern, Central and Western) has the authority to nominate two diversity candidates for each election, and these candidates are not directly voted on, but approved or not by the voting members. At present, 31% of the Council are the diversity delegates.

    The NEC is currently looking for a new co-chair committed to improving the diversity within the HUPO leadership. HUPO members interested in this position and in making their vision and ideas a reality are encouraged to apply! Contact

  • 20 Apr 2021 12:24 PM | Anonymous member (Administrator)

    Connect with leaders of the Biology/Disease-Driven Human Proteome Project (B/D-HPP) at their first PTMs in Human Disease webinar focused on showcasing approaches to investigate post-translational modifications (PTMs). This webinar will consist of seven (7) presentations and a panel discussion among speakers and participants.

    See list of speakers and presentation topics here: Webinar Flyer

    Date: Monday, April 26, 2021

    Time: 0600 PST; 0900 EST; 1300 UTC (Three (3) hours) Find your local time zone

    Zoom meeting link:

  • 30 Mar 2021 4:16 PM | Anonymous member (Administrator)

    Sanjeeva Srivastava, IIT Bombay, India

    The flourishing field of advanced multi-omics technologies opened new avenues for understanding health and disease biology, specifically identifying disease-specific biomarkers and developing potential therapies. Among all multi-omics technologies, Proteomics has time and again proved vital to provide insight into disease pathology. The workflow of designing a proteomics experiment and making sense out of that data is always challenging, especially for beginners in the field.

    To aid these scientists and students, Prof. Sanjeeva Srivastava from IIT Bombay, in collaboration with DST, India, organized a two weeks’ workshop on ‘Basics and Advanced Proteomics Approaches Workshop’ from 15th to 26th February 2021 to spread the knowledge in high throughput proteomics technologies and the data analysis strategies using advanced software like- MaxQuant, Proteome Discoverer, MetaboAnalyst and Reactome.

    This event was a success due to the eminent scientists and experts from the industry from India and Abroad who shared their research experience, knowledge, and expertise in that field. In addition to that, Participants, mainly faculties from different universities/ institutions of India, made the workshop more interactive rather than lecture series. All participants were provided some group projects to make them more confident in data analysis and to build collaboration between them in the near future.

    The first week of the workshop was conducted to enlighten the participants’ knowledge in MS-based proteomics, various approaches of quantitative proteomics like- gel-free and gel-based proteomics, and acquaint them with software for primary proteomic data analysis. In the morning sessions, plenary speakers including Prof. Marc Wilkins, Matthias Ulhén, Bernhard Küster, and Prof. Mark Baker, other eminent scientists including Prof. Surekha Zingde, Utpal Tatu, Mathias Wilhelm, Anthony Purcell gave an insightful talk on various aspects of proteomics and its applicability in clinical research. The afternoon sessions were designed to give the participants a hands-on experience in sample preparation for quantitative proteomics, including protein extraction and digestion, sample run in the mass spectrometer, monitoring of sample run, and primary and secondary analysis of proteomics data. The second week of the workshop was designed to introduce participants to the high throughput proteomics technologies like targeted proteomics, label-free biosensors like SPR, BLI, protein microarray, and network analysis to infer the biological significance from the MS data. In this week, participants got the opportunity to hear from esteemed scientists and researchers in the proteomics field Prof. Xiaobo Yu, Prof. Henning Hermjakob, Dr. Jau-song Yu, Dr. Suman Thakur. This week was more enriched with tech-talks; Mr. Michael Johnson, Dr. Rodrigo Barderas, Dr. Tian-Hua Wang, Dr. Debadeep Bhattacharyya shared their research work and the developed techniques to elevate the proteomic research. The major attraction of the second week was the group project which made participants more familiar with handling the mass spectrometric data.

    Nowadays, it has become essential to upgrade us with current trends and advances in proteomics technologies to facilitate the translation of lab research to clinics. Herewith, this two weeks long workshop gave the participants an insight to use these high-throughput proteomics technologies for the progression of the clinical research.

    All the workshop recordings are available at Proteomics Workshop YouTube video playlist link:

  • 25 Mar 2021 4:19 PM | Anonymous member (Administrator)

    The HUPO B/D-HPP Executive Committee is excited to announce an upcoming human proteome webinar organized by B/D-HPP in April/May 2021! The webinar will be the start of a series of online events to highlight recent progresses in proteome research from leading investigators around the globe.

    The theme of the first webinar will be "PTMs in Human Disease". This 3-hour event will feature talks from ~5 to 7 leading experts on proteomics approach toward multiple types of common and rare post-translational modifications in the human proteome. More information including speaker list, title, webinar time and weblink will be posted in the coming weeks. Please stay tuned!

  • 02 Mar 2021 4:44 PM | Anonymous member (Administrator)

    Did you know HUPO has a YouTube channel? From the 2017 world congress welcome address by former 47th Vice President of the United States Joseph R. Biden Jr., to a series of interviews on perspectives in proteomics, check out videos recorded at our past congresses on YouTube.


    An interview series of proteomics experts has been undertaken over the last several HUPO world congresses, and describe the challenges and goals of current basic and clinical research in the proteomics field. This perspective series is directed by Prof. Sanjeeva Srivastava, IIT Bombay, Mumbai.

  • 02 Mar 2021 4:43 PM | Anonymous member (Administrator)

    July 6-8, 2021

    Abstract submission and early bird registration are now open for the British Society for Proteome Research (BSPR) Interact 2021 meeting. The conference features prominent and upcoming scientists from the UK and across the globe, presenting the latest research and methodology in the field of proteomics, as well as participating in round table discussions.

    For more information, including on how to register and submit your abstract, please visit To stay up to date, follow the BSPR on Twitter and Facebook @UKBspr, and join the BSPR LinkedIn group @BSPR - British Society for Proteome Research.

  • 02 Mar 2021 4:42 PM | Anonymous member (Administrator)

    Did you attend HUPO Connect? Don't forget you have access to all recordings until March 31, 2021. Didn't attend HUPO Connect? On-demand recordings are still available for purchase. Learn more..

  • 02 Mar 2021 4:42 PM | Anonymous member (Administrator)

    The Nominations and Elections Committee will be seeking candidates to serve on HUPO Council for a three-year term beginning January 2022 (2022-2024). Call for nominations will open on Thursday, March 25, 2021. Stay tuned for more updates in the weeks to come!

  • 02 Mar 2021 4:41 PM | Anonymous member (Administrator)

    Do you know someone who has made an impact in the field of proteomics and deserves recognition for it? Nominate them for a HUPO award. Submission deadline is Friday, April 30, 2021. Click here to review the nomination requirements and submit...

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