The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML

Targeting the Mitochondrial Peptidase Neurolysin in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) cells and stem cells have unique mitochondrial characteristics with an increased reliance on oxidative phosphorylation (OXPHOS). Through a genetic screen to find novel mitochondrial targets in AML, we identified the mitochondrial peptidase, neurolysin (NLN). NLN is a metallopeptidase whose mitochondrial function is not well understood and whose role in AML has not been reported. We analyzed the expression of NLN in AML cells and normal hematopoietic cells. NLN gene expression was enhanced in 41% of AML samples and overexpression was confirmed by immunoblotting. Next, we assessed the effects of knocking down NLN in AML cell lines. NLN knockdown reduced AML growth by up to 70%, clonogenic growth by up to 80%, and engraftment into mouse marrow by 90%. We next identified NLN’s mitochondrial interactors by BioID-MS. NLN interacted extensively with the respiratory chain and NLN knockdown reduced OXPHOS. Moreover, NLN knockdown impaired the formation of respiratory chain supercomplexes (RCS), which promote efficient oxidative metabolism. RCS have not been previously studied in leukemia. We found that RCS assembly was increased in a subset of AML patients compared to normal hematopoietic cells and positively correlated with NLN protein expression (R2 = 0.80, pPh.D

Targeting neurolysin in acute myeloid leukemia

We recently identified the mitochondrial peptidase, neurolysin (NLN), as a top hit in an acute myeloid leukemia (AML) viability screen. Using chemical and genetic approaches, we demonstrated that loss of NLN disrupted respiratory chain supercomplex assembly and impaired oxidative metabolism in AML. Moreover, inhibition of NLN in vitro and in vivo reduced the growth of AML cells

Piloting a long distance clinician scientist trainee mentorship match in Canada

Clinician scientists are physicians who are uniquely trained to bridge the gap between scientific discovery and clinical practice. However, the challenges of integrating research and medicine are often not directly addressed in the clinician scientist training programs. Furthermore, the demanding training path is financially and personally daunting. Previous studies have shown that MD/PhD trainees value the advice and expertise of senior mentors in navigating their academic career path. Despite this demand for mentors, there is a lack of formal mentorship initiatives at the institutional level across Canada. Recently, MD/PhD trainees have attempted to address this issue by implementing a nationwide mentorship match, with the aim of making mentorship more accessible to trainees across Canada

Addressing the need for a new generation of young translational researchers that focuses on societal impact: The Apollo Toronto Story

Translational research (TR) is a multidirectional and multidisciplinary integration of basic research, patient-oriented research and population-based research, with the long-term goal of improving human health. Unfortunately, the current scientific training system does not adequately align with the goals of TR. To address this issue, an organization called Apollo Toronto was established at the University of Toronto in Toronto, Ontario. Apollo Toronto is a medical student-run international collaborative project between the Eureka Institute for Translational Medicine and the University of Toronto (one of Eureka Institute’s partner universities), and provides a general overview of TR to interested medical and graduate students. Through local and international initiatives, the various Apollo chapters (including Apollo Toronto) aim to establish a network of trainees equipped to address systemic issues that impede the translation of an ever-growing body of scientific literature into health solutions

Scientific Overview on CSCI-CITAC Annual General Meeting and 2018 Young Investigators’ Forum

The 2018 Annual General Meeting (AGM) and Young Investigators’ Forum (YIF) of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was held in Toronto, Ontario on November 19–20, 2018, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for the meeting was “Prepare for Success—Things to Master Now for Clinician Scientists in Training”; with lectures and workshops that were designed to provide knowledge and hands-on skills to navigate life as a clinician investigator. The opening remarks were by Jason Berman (President of CSCI), Josh Abraham (President of CITAC/ACCFC) and Nicola Jones (University of Toronto Clinician Investigator Symposium Chair). The keynote speakers were Dr. Ruth Ann Marrie (University of Manitoba), who received the Distinguished Scientist Award, Dr. Davinder Jassal (University of Manitoba), who received the CSCI-RCPSC Henry Friesen Award, and Dr. Aleixo Muise (University of Toronto), who received the Joe Doupe Young Investigator Award. Dr. Minna Woo (University of Toronto), Canada Research Chair in Diabetes Signal Transduction, delivered the keynote lecture “From Onion Cells to Single Cell Seq—A Constant Change in Lenses: A perspective of an evolving clinician scientist”. The workshops, focusing on career development for clinician-scientists, were hosted by Drs. Robert Chen, Stephen Juvet, Lorraine Kalia, Phyllis Billia, Neil Goldenberg, Nicola Jones, Srdjanaa Filipovic, Jason Berman, Josh Abraham, Melanie Szweras, Joseph Ferenbok and Uri Tabori. The AGM also included presentations from clinician investigator trainees from across the country, and these abstracts are summarized in this review. Over 80 abstracts were showcased at this year’s meeting during the poster session, with six outstanding abstracts selected for oral presentations during the President’s Forum

Scientific overview on CSCI-CITAC Annual General Meeting and 2017 Young Investigators’ Forum

The 2017 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national Annual General Meeting (AGM) held in Toronto, Ontario November 20–22, 2017, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for this year’s meeting was “Roll up your sleeves—How to manage your physician scientist career”, emphasizing lectures and workshops that were designed to provide tools for being proactive and successful in career planning. The keynote speakers were Dr. Rod McInnes (McGill University and Canadian Institutes of Health Research Acting President), who was the Distinguished Scientist Award recipient, Dr. David Goltzman (McGill University), who was the 2017 Henry Friesen Award recipient, Dr. Gillian Hawker (University of Toronto), Dr. Mike Sapieha (Université de Montréal), who was the 2017 Joe Doupe Award recipient, and Dr. Alex MacKenzie (Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa). The workshops, focusing on career development for clinician scientists, were hosted by Dr. Lisa Robinson, Dr. Nicola Jones, Kevin Vuong, Fran Brunelle, Dr. Jason Berman and Dr. Alan Underhill. Further to this, the Young Investigators’ Forum encompasses presentations from scientist-clinician trainees from across the country. All scientific abstracts are summarized in this review. There were over 100 abstracts showcased at this year’s meeting during the highlighted poster sessions, with six outstanding abstracts selected for oral presentations during the President’s Forum

Male-specific conditioned pain hypersensitivity in mice and humans

Pain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24 hr and was only present in males of both species. In mice, context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mz isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress