1. Biochemistry and Chemical Biology
  2. Cell Biology
Download icon

Metabolism: Warburg’s vision

  1. James B Hurley  Is a corresponding author
  1. University of Washington, United States
  • Cited 1
  • Views 2,017
  • Annotations
Cite this article as: eLife 2017;6:e29217 doi: 10.7554/eLife.29217


Genetic tools help to dissect the relationship between aerobic glycolysis and anabolic metabolism in the retinas of mice.

Main text

Rod-shaped cells at the back of our eyes allow us to see in dim light. Each day, around dawn, these rod cells shed their tips (LaVail, 1976), and the lost material is replaced with newly built proteins and other macromolecules made further down in the same cell (Anderson et al., 1980; Young, 1967).

Cancer cells growing in a tumor also have a high demand for newly built macromolecules. In the early 1920s, the German physiologist Otto Warburg reported on a specialized type of metabolism that converts most of the glucose taken up by a cell into lactate, rather than carbon dioxide and water as usually happens, even when oxygen is abundant (Warburg et al., 1924). Two of the tissues in which Warburg discovered this type of metabolism, which is often referred to as "aerobic glycolysis", were the very same tissues introduced above, retinas and tumors.

The building of complex macromolecules from simpler building blocks is referred to as anabolism. Recently studies into the metabolism of cancer cells have begun to reveal biochemical details that may link aerobic glycolysis and anabolic activity (Vander Heiden and DeBerardinis, 2017). One of the remarkable features of cancer cells discovered in these studies is that they often produce specific versions (or isoforms) of the enzymes that carry out glycolysis, namely pyruvate kinase (PKM2) and lactate dehydrogenase (LDHA). Not surprisingly, these same isoforms are present in rod cells (Casson et al., 2016; Lindsay et al., 2014; Rajala et al., 2016; Rueda et al., 2016). Now, in eLife, Constance Cepko and colleagues at Harvard Medical School – including Yashodhan Chinchore as first author – report how these two glycolytic enzymes contribute to anabolic metabolism in rod cells from mice (Chinchore et al., 2017).

First, Chinchore et al. inactivated LDHA and PKM2 in mouse rod cells, either with inhibitors or by reducing expression of the genes that encode the enzymes. The resulting rod cells were shorter than normal, as if they did not have enough anabolic activity to counteract the shedding of their tips (Figure 1). In support of this idea, when the mice were kept in constant darkness (which suppresses shedding and renewal of the outer segments), inactivating LDHA or PKM2 had less of an effect. Chinchore et al. then engineered mice in which some cells in the retina made less LDHA or PKM2 while the others were normal. In these 'mosaic' retinas, the only rods that were shorter were the ones with less LDHA or PKM2. This suggests that the enzymes promote anabolism only in the cell in which they are made.

Manipulation of glycolytic enzymes sheds light on the link between aerobic glycolysis and anabolic metabolism.

(A) The tip of the outer segment of a rod cell in the retina regularly sheds and needs to be replaced. Anabolic activity (green) in the same cell builds the macromolecules needed to replace the lost material. Two glycolytic enzymes, called PKM2 and LDHA (light blue circles), are thought to drive the anabolic metabolism of rod cells. (B) Reducing the expression of either of the genes for these enzymes results in rod cells with shorter outer segments, most likely because there is not enough anabolic activity to counteract the shedding. (C) Keeping mice in constant darkness suppresses the shedding and means that rod cells that lack LDHA or PKM2 still have outer segments of a normal length.

Chinchore et al. were concerned that the complete loss of PKM2 or LDHA might have effects that were so devastating that even the essential 'housekeeping' roles of glycolysis in the cell could be compromised. To address that concern, they also used a more 'surgical' approach that specifically slowed glycolysis without eliminating the entire pathway. Fructose-2,6-bisphosphate is an activator of glycolysis. To decrease this chemical in rod cells, Chinchore et al. overexpressed a protein specifically in rods that removes an essential phosphate group from this activator. Slowing glycolysis by this strategy made the rod cells shorter than normal, indicating that flux through the glycolysis pathway is key.

So, what makes PKM2 and LDHA different from other isoforms so that cells requiring rapid growth use them and not the other isoforms? Previous studies showed that these enzymes can be regulated by tyrosine phosphorylation to promote aerobic glycolysis (Hitosugi et al., 2009; Jin et al., 2017). Moreover, exposure to light – which increases the need for anabolic activity – enhances phosphorylation of PKM2 in the retinas of mice (Rajala et al., 2016). Chinchore et al. confirmed this result and then looked for signaling pathways that, when blocked, reduced how much PKM2 was phosphorylated in rod cells. They found that the pathway that responds to fibroblast growth factor (FGF) can control the phosphorylation of PKM2 and LDHA in mouse retinas. The tissue that normally is immediately adjacent to the rod cells, the retinal pigment epithelium, can influence the amount of FGF that a retina is exposed to in an eye. Chinchore et al. found that culturing mouse retinas with this tissue, or with some FGF, boosts how much lactate is produced.

By manipulating the expression of genes involved in aerobic glycolysis in mouse retinas, Chinchore et al. have further revealed how aerobic glycolysis relates to anabolic metabolism. They also show that disrupting any of three different steps in glycolysis can diminish anabolic capacity and cause the rod cells to become shorter. Each of the disruptions tested would have a different biochemical effect on the glycolytic pathway, but what they have in common is that they all cause less lactate to be produced. It is not yet clear why this would compromise anabolic activity, but the genetic tools developed by Chinchore et al. to manipulate glycolysis in rod cells provide new opportunities to answer this question.


    1. Rueda EM
    2. Johnson JE
    3. Giddabasappa A
    4. Swaroop A
    5. Brooks MJ
    6. Sigel I
    7. Chaney SY
    8. Fox DA
    The cellular and compartmental profile of mouse retinal glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and ~P transferring kinases
    Molecular Vision 22:847–885.
    1. Warburg O
    2. Posener K
    3. Negelein E
    On the metabolism of carcinoma cells
    Bioschemische Zeitschrift 152:309–344.

Article and author information

Author details

  1. James B Hurley

    1. Department of Biochemistry, University of Washington, Seattle, United States
    2. Department of Ophthalmology, University of Washington, Seattle, United States
    For correspondence
    Competing interests
    The author declares that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7754-0705

Publication history

  1. Version of Record published: July 6, 2017 (version 1)


© 2017, Hurley

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 2,017
    Page views
  • 257
  • 1

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Biochemistry and Chemical Biology
    Gajanan S Patil et al.
    Research Article Updated

    Fatty acyl-AMP ligases (FAALs) channelize fatty acids towards biosynthesis of virulent lipids in mycobacteria and other pharmaceutically or ecologically important polyketides and lipopeptides in other microbes. They do so by bypassing the ubiquitous coenzyme A-dependent activation and rely on the acyl carrier protein-tethered 4′-phosphopantetheine (holo-ACP). The molecular basis of how FAALs strictly reject chemically identical and abundant acceptors like coenzyme A (CoA) and accept holo-ACP unlike other members of the ANL superfamily remains elusive. We show that FAALs have plugged the promiscuous canonical CoA-binding pockets and utilize highly selective alternative binding sites. These alternative pockets can distinguish adenosine 3′,5′-bisphosphate-containing CoA from holo-ACP and thus FAALs can distinguish between CoA and holo-ACP. These exclusive features helped identify the omnipresence of FAAL-like proteins and their emergence in plants, fungi, and animals with unconventional domain organizations. The universal distribution of FAALs suggests that they are parallelly evolved with FACLs for ensuring a CoA-independent activation and redirection of fatty acids towards lipidic metabolites.

    1. Biochemistry and Chemical Biology
    Urszula Nowicka et al.
    Research Article Updated

    Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.