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Phang 2023 MiP2023

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MitoGlobal Events
MiPschool 2023

Phang 2023 MiP2023

Phang Howard J
Screening marine natural products for bioenergetic effects in human cell models.

Link: MiPschool Obergurgl 2023

Phang Howard J (2023)

Event: MiPschool Obergurgl 2023

Authors: Phang Howard J, Gerwick W, Molina Anthony JA

Mitochondrial bioenergetic decline is a well known biological hallmark of aging, suggesting that mitochondria-targeting therapeutics have great potential in treating age-related diseases and conditions [1]. Despite this, their efficacy within the context of human aging remains largely unknown. We sought to develop a phenotypic screening platform to identify agents that directly modulate mitochondrial function in human cells.
Marine natural products (MNP) represent a large, under-explored chemical space with immense therapeutic potential [2]. We screened a MNP library of 125 pure compounds at 10, 1, and 0.1 ยตg/mL incubated for 24 hours with with primary human dermal fibroblasts (pHDF) as summarized in Figure 1. We leveraged the San Diego Nathan Shock Center which houses 50+ pHDF lines derived from healthy donors across a spectrum of adult age. Cultured pHDF retain age-related phenotypes including mitochondrial bioenergetic decline, which presents a robust opportunity to identify bioenergetic effects within the context of human aging [3]. Thus, we used pHDF from a donor representative of an โ€œolderโ€ phenotype (74 years of age) to ensure aging relevance.
We identified numerous compounds that modulate mitochondrial function in a dose-dependent manner. Our primary outcomes were change in basal or maximal respiration using high throughput respirometry (Agilent Seahorse XFe96). This screening platform successfully identified compounds with stimulatory as well as inhibitory effects on respiratory capacity. Future steps include further validation of hit compounds using high-resolution respirometry on the Oroboros O2k. These studies will elucidate mechanistic effects on the electron transfer system as well as effects on cells of different donor ages.

  1. Murphy MP, Hartley RC (2018) Mitochondria as a therapeutic target for common pathologies.
  2. Liang X, Luo D, Luesch H (2018) Advances in exploring the therapeutic potential of marine natural products.
  3. Auburger G, Klinkenberg M, Drost J, Marcus K, Morales-Gordo B, Kunz WS, Brandt U, Broccoli V, Reichmann H, Gispert S, Jendrach M (2012). Primary Skin Fibroblasts as a Model of Parkinson's Disease.

โ€ข Keywords: marine natural products, drug discovery, screening

โ€ข O2k-Network Lab: US CA San Diego Molina AJA


Figure 1. Workflow of respirometry screen


Phang Howard J1, Gerwick W1,2, Molina AJA3
  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, Univ of California, San Diego, La Jolla, CA, USA
  2. Scripps Institute of Oceanography, Univ of California, San Diego, La Jolla, CA, USA
  3. Dept of Medicine, Univ of California, San Diego, La Jolla, CA, USA
Corresponding author: [email protected]

Labels: Pathology: Aging;senescence 

Organism: Human  Tissue;cell: Fibroblast 

Event: E1