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I am aware of the Malate–Aspartate Shuttle, but something is not clear to me and different sources seem to contradict each other. Some show oxaloacetate (OAA) being reduced to malate in the mitochondrial inter-membrane space (IMS), whereas others show the reduction happening in the cytosol.

Where does the OAA → malate reduction happen? i.e., can OAA cross the outer mitochondrial membrane (from the cytosol into the IMS) so that it can be reduced in the IMS, or must it be reduced in the cytosol before crossing either of the two mitochondrial membranes?

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    $\begingroup$ I've edited your question a little. I defined the abbreviations you used. This makes the question clearer and I mention it in the hope that it will help you in formulating future questions. (It is not necessary to abbreviate malate to mal to save three characters, so I spelled this out in full.) $\endgroup$
    – David
    Jan 31, 2017 at 11:24

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In general the outer mitochondrial membrane is thought to be basically permeable (through porins) to small molecules such as OAA. As is typical in biology, the situation may actually be more complex -- see for example this paper. But I think the default assumption is that metabolites freely cross the mitochondrial outer membrane.

You might also ask whether either the mitochondrial MDH or the cytoplasmic MDH enzyme is likely to be found or be active inside the intermembrane space.

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  • $\begingroup$ Good point about considering which enzyme is active. Thank you for the concise answer. $\endgroup$
    – electronpusher
    Feb 3, 2017 at 18:54
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Oxaloacetate (OAA) cannot cross the inner mitochondrial membrane.

The process of oxidative phosphorylation and the electron transport system (ETS) occur in the mitochondrion, whereas $\ce{NADH}$ generated by the reduction of $\ce{NAD+}$ in glycolysis is in the cytoplasm. The problem is that the inner mitochondrial membrane is not permeable to $\ce{NADH}$ , so a shuttle system is required for the transport of the reducing equivalents through the mitochondrial membrane. There are two of these, one of which is the ‘Malate–Aspertate’ shuttle.

The Malate-Aspertate Shuttle

In the process (see above) oxaloacetate (OAA) takes up the reducing equivalents from $\ce{NADH}$ to form malate in a reaction catalysed by malate dehydrogenase. The inner mitochondrial membrane is permeable to malate, which passes through carrier proteins (Malate-$\alpha$-ketogluterate transporter) into the mitochondrial matrix where it is converted back to OAA. As this happens the concentration of OAA decreases in the inter-membrane space, and as OAA cannot pass directly through the inner mitochondrial membrane it is converted into aspartate in the mitochondrial matrix by reacting with glutamate to produce $\alpha$-ketoglutarate and aspartate. The aspartate then travels to the inter-membrane space through specific carriers(Glutamate-aspartate Transporter). In the inter membrane space the aspartate combines with $\alpha$-ketoglutarate to form glutamate and OAA (the reverse of what happened in the mitochondrial matrix). Thus the concentration of OAA is maintained in the inter-membrane space, and the reaction continues.

Conclusion

OAA is converted into malate in the inter-membrane space. In the mitochondrial matrix malate is converted back to OAA, as illustrated in the illustration below.

Malate-Aspartate Shuttle

Image source : Malate–Aspartate Shuttle, Wikipedia

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    $\begingroup$ I have edited your answer extensively. Although what you wrote about OAA and malate seems reasonable, your remarks about reduction were incorrect (reduction is the addition of an electron, not an electron and a proton) and there is no such molecule as NADH+. Further an illustration in Wikipedia cannot prove a 'fact'. A fact is a fact, and is established by experiment. $\endgroup$
    – David
    Jan 31, 2017 at 11:29
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    $\begingroup$ Thank You for the edit. But I have one question, addition of an electron is definitely reduction, but can't I say the addition of an hydrogen as addition of an electron and proton, in that case it is also reduction. I am not arguing ( and definitely it was my fault) but it can be said like that. And about the 'fact' - some people prefer such sources , they think that an answer is incomplete without a citation from a notable site or book and they don't even judge whether the answer is reasonable or not. $\endgroup$
    – jyoti proy
    Jan 31, 2017 at 17:19
  • $\begingroup$ This is the textbook answer, but there are also studies suggesting that oxaloacetate can cross the inner mitochondrial membrane, see for example sciencedirect.com/science/article/pii/0003986177900200 It might be that this is cell type and/or condition dependent. Or perhaps the transport rate for oxaloacetate is too slow. $\endgroup$
    – Roland
    Jan 31, 2017 at 19:05
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    $\begingroup$ In reply to your response to my comment. 1. On the reduction reaction. First, it is not necessary to discuss it in answering this question, which doesn't even mention it. It is, of course, relevant to explain that the problem is the transfer of NADH into the mitochondrion and NAD+ out. But, as I wrote, there is no such molecule as NADH+, so this mistake detracted from the virtues of the answer. Indeed the figures you reproduce show NADH. As for your question, there is no addition of a proton, but of two hydrogen atoms, and the balanced equation is: NAD+ + 2H ⇋ NADH + H+. $\endgroup$
    – David
    Jan 31, 2017 at 20:31
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    $\begingroup$ jyoti: Thank you for your detailed explanation. However, it does not directly answer my question and I tried to show I was already assuming this information by staying "I am aware of the Malate-Aspartate Shuttle". My interest in whether OAA can cross the /outer/ mitochondrial membrane. You seem to have deliberately avoided addressing this, mentioning how NADH must be imported then suddenly you speak about OAA already being in the IMS (without mentioning how it got there). $\endgroup$
    – electronpusher
    Feb 1, 2017 at 4:47

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